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Sample records for attenuates hypobaric hypoxia

  1. Rearing of silkworm under hypobaric and hypoxia conditions

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    Hashimoto, Hirofumi; Nakayama, Shin; Yamashita, Masamichi; Space Agriculture Task Force, J.

    In order to investigate of a possibility of utilizing silkworm for the space agriculture, rearing of silkworms was examined under hypobaric and hypoxia conditions. In terms of structural mechanics, the lower inner pressure of Martian greenhouse has advantage to reduce requirements on physical properties of mechanical member of the pressurized structure. The main objective of this study is to know the influence of lower total pressure and hypoxia condition on silkworm. Silkworms are reared under following four hypobaric and hypoxia conditions, 10kPa pure oxygen, 20kPa pure oxygen, 10kPa oxygen and 10kPa nitrogen, and 10kPa oxygen and 90kPa nitrogen. After rearing them to pupa stage, growth of silkworms was found poor under all hypobaric hypoxia conditions compared to those grown under the normal atmospheric condition; the control group. The growth under total pressure of 20kPa is slightly fast.

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

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    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

  3. Effect of Ca2EDTA on zinc mediated inflammation and neuronal apoptosis in hippocampus of an in vivo mouse model of hypobaric hypoxia.

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    Udayabanu Malairaman

    Full Text Available BACKGROUND: Calcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage. METHODS: Adult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca2EDTA (1.25 mM/kg i.p daily for four days. The effects of Ca2EDTA on apoptosis (caspases activity and DNA fragmentation, pro-inflammatory markers (iNOS, TNF-α and COX-2, NADPH oxidase activity, poly(ADP ribose polymerase (PARP activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain. RESULTS: Hypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6. Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca2EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus. CONCLUSION: We propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia

  4. Blueberry Extracts Protect Testis from Hypobaric Hypoxia Induced Oxidative Stress in Rats

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    Andrea Zepeda

    2012-01-01

    Full Text Available Exposure to hypobaric hypoxia causes oxidative damage to male rat reproductive function. The aim of this study was to evaluate the protective effect of a blueberry extract (BB-4 in testis of rats exposed to hypobaric hypoxia. Morphometric analysis, cellular DNA fragmentation, glutathione reductase (GR, and superoxide dismutase (SOD activities were evaluated. Our results showed that supplementation of BB-4 reduced lipid peroxidation, decreased apoptosis, and increased GR and SOD activities in rat testis under hypobaric hypoxia conditions . Therefore, this study demonstrates that blueberry extract significantly reduced the harmful effects of oxidative stress caused by hypobaric hypoxia in rat testis by affecting glutathione reductase and superoxide dismutase activities.

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

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    Neuhaus C; Hinkelbein J

    2014-01-01

    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 ...

  6. Hypobaric Hypoxia: Effects on Intraocular Pressure and Corneal Thickness

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    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.

  7. Relationship between mitochondrial haplogroup and physiological responses to hypobaric hypoxia.

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    Motoi, Midori; Nishimura, Takayuki; Egashira, Yuka; Kishida, Fumi; Watanuki, Shigeki

    2016-04-29

    We aimed to investigate the relationship between mtDNA polymorphism and physiological responses to hypobaric hypoxia. The study included 28 healthy male students, consisting of 18 students in haplogroup D and 10 in haplogroup M7+G. Measurement sensors were attached to the participants for approximately 30 min in an environment with a temperature of 28 °C. After resting for 15 min, the programmed operation of the hypobaric chamber decreased the atmospheric pressure by 11.9 Torr every minute to simulate an increase in altitude of 150 m until 9.7 Torr (equivalent to 2500 m) and then decreased 9.7 Torr every minute until 465 Torr (equivalent to 4000 m). At each altitude, the pressure was maintained for 15 min and various measurements were taken. Haplogroup D showed higher SpO2 (p < 0.05) and significantly higher SpO2 during the pressure recovery period when compared with haplogroup M7+G. The distal skin temperature was higher in haplogroup D when compared with M7+G. These results suggested that haplogroup D maintained SpO2 at a higher level with higher peripheral blood flow during acute hypobaric exposure.

  8. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

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    Khushbu Jain

    2015-01-01

    Full Text Available Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH. The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

  9. Beneficial effects of intermittent hypobaric hypoxia on the body

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    Yi ZHANG; Zhao-nian ZHOU

    2012-01-01

    Myocardial ischemia and reperfusion (I/R) is a common problem in clinic and there is no satisfactory method for prevention or treatment of I/R injury so far.Chronic intermittent hypobaric hypoxia (CIHH),similar to the concept of ischemia preconditioning(IPC)or altitude hypoxia adaptation (AHA),has been recognized to confer a protective effect on heart against I/R injury with a longer protective effect than IPC and a less adverse effect than AHA.It has been proved that CIHH increases myocardial tolerance to ischemia or hypoxia,reserving cardiac function and preventing arrhythmia during I/R.Multiple mechanisms or pathway underlying the cardiac protection of ClHH have been proposed,such as induction of heatshock protein,enhancement of myocardial antioxidation capacity,increase of coronary flow and myocardial capillary angiogenesis,activation of adenosine triphosphate (ATP)-sensitive potassium channels,inhibition of mitochondrial permeability transition pores,and activation of protein kinase C (PKC) and induced nitric oxide synthase (iNOS).In addition,CIHH has been found having many beneficial effects on the body,such as promotion of health,increase of oxygen utilization,and prevention or treatment for some diseases.The beneficial effects of ClHH and potential mechanisms are reviewed mainly based on the researches performed by our group.

  10. Intermittent hypobaric hypoxia combined with aerobic exercise improves muscle morphofunctional recovery after eccentric exercise to exhaustion in trained rats.

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    Rizo-Roca, D; Ríos-Kristjánsson, J G; Núñez-Espinosa, C; Santos-Alves, E; Gonçalves, I O; Magalhães, J; Ascensão, A; Pagès, T; Viscor, G; Torrella, J R

    2017-03-01

    Unaccustomed eccentric exercise leads to muscle morphological and functional alterations, including microvasculature damage, the repair of which is modulated by hypoxia. We present the effects of intermittent hypobaric hypoxia and exercise on recovery from eccentric exercise-induced muscle damage (EEIMD). Soleus muscles from trained rats were excised before (CTRL) and 1, 3, 7, and 14 days after a double session of EEIMD protocol. A recovery treatment consisting of one of the following protocols was applied 1 day after the EEIMD: passive normobaric recovery (PNR), a 4-h daily exposure to passive hypobaric hypoxia at 4,000 m (PHR), or hypobaric hypoxia exposure followed by aerobic exercise (AHR). EEIMD produced an increase in the percentage of abnormal fibers compared with CTRL, and it affected the microvasculature by decreasing capillary density (CD, capillaries per mm(2)) and the capillary-to-fiber ratio (CF). After 14 days, AHR exhibited CD and CF values similar to those of CTRL animals (789 and 3.30 vs. 746 and 3.06) and significantly higher than PNR (575 and 2.62) and PHR (630 and 2.92). Furthermore, VEGF expression showed a significant 43% increase in AHR when compared with PNR. Moreover, after 14 days, the muscle fibers in AHR had a more oxidative phenotype than the other groups, with significantly smaller cross-sectional areas (AHR, 3,745; PNR, 4,502; and PHR, 4,790 µm(2)), higher citrate synthase activity (AHR, 14.8; PNR, 13.1; and PHR, 12 µmol·min(-1)·mg(-1)) and a significant 27% increment in PGC-1α levels compared with PNR. Our data show that hypoxia combined with exercise attenuates or reverses the morphofunctional alterations induced by EEIMD.NEW & NOTEWORTHY Our study provides new insights into the use of intermittent hypobaric hypoxia combined with exercise as a strategy to recover muscle damage induced by eccentric exercise. We analyzed the effects of hypobaric exposure combined with aerobic exercise on histopathological features of muscle

  11. Protection of Pentoxifylline against Testis Injury Induced by Intermittent Hypobaric Hypoxia

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    Chen Yao

    2016-01-01

    Full Text Available To investigate the effect of pentoxifylline (PTX on spermatogenesis dysfunction induced by intermittent hypobaric hypoxia (IHH and unveil the underlying mechanism, experimental animals were assigned to Control, IHH+Vehicle, and IHH+PTX groups and exposed to 4 cycles of 96 h of hypobaric hypoxia followed by 96 h of normobaric normoxia for 32 days. PTX was administered for 32 days. Blood and tissue samples were collected 7 days thereafter. Serum malondialdehyde levels were used to assess lipid peroxidation; ferric-reducing antioxidant power (FRAP, superoxide dismutase, and catalase and glutathione peroxidase enzyme activities were assessed to determine antioxidant capacity in various samples. Testis histopathology was assessed after hematoxylin-eosin staining by Johnsen’s testicular scoring system. Meanwhile, testosterone synthase and vimentin amounts were assessed by immunohistochemistry. Sperm count, motility, and density were assessed to determine epididymal sperm quality. IHH treatment induced significant pathological changes in testicular tissue and enhanced serum lipid peroxide levels, while reducing serum FRAP, antioxidant enzyme activities, and testosterone synthase expression. Moreover, IHH impaired epididymal sperm quality and vimentin structure in Sertoli cells. Oral administration of PTX improved the pathological changes in the testis. IHH may impair spermatogenesis function of testicular tissues by inducing oxidative stress, but this impairment could be attenuated by administration of PTX.

  12. The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials.

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    Coppel, Jonny; Hennis, Philip; Gilbert-Kawai, Edward; Grocott, Michael Pw

    2015-01-01

    Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting.

  13. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment.

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    Hota, Sunil Kumar; Barhwal, Kalpana; Baitharu, Iswar; Prasad, Dipti; Singh, Shashi Bala; Ilavazhagan, Govindasamy

    2009-04-01

    Hypobaric hypoxia induced memory impairment has been attributed to several factors including increased oxidative stress, depleted mitochondrial bioenergetics, altered neurotransmission and apoptosis. This multifactorial response of the brain to hypobaric hypoxia limits the use of therapeutic agents that target individual pathways for ameliorating hypobaric hypoxia induced memory impairment. The present study aimed at exploring the therapeutic potential of a bacoside rich leaf extract of Bacopa monniera in improving the memory functions in hypobaric conditions. The learning ability was evaluated in male Sprague Dawley rats along with memory retrieval following exposure to hypobaric conditions simulating an altitude of 25,000 ft for different durations. The effect of bacoside administration on apoptosis, cytochrome c oxidase activity, ATP levels, and oxidative stress markers and on plasma corticosterone levels was investigated. Expression of NR1 subunit of N-methyl-d-aspartate receptors, neuronal cell adhesion molecules and was also studied along with CREB phosphorylation to elucidate the molecular mechanisms of bacoside action. Bacoside administration was seen to enhance learning ability in rats along with augmentation in memory retrieval and prevention of dendritic atrophy following hypoxic exposure. In addition, it decreased oxidative stress, plasma corticosterone levels and neuronal degeneration. Bacoside administration also increased cytochrome c oxidase activity along with a concomitant increase in ATP levels. Hence, administration of bacosides could be a useful therapeutic strategy in ameliorating hypobaric hypoxia induced cognitive dysfunctions and other related neurological disorders.

  14. Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin-proteasome pathway and calpains.

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    Chaudhary, Pooja; Suryakumar, Geetha; Prasad, Rajendra; Singh, Som Nath; Ali, Shakir; Ilavazhagan, Govindsamy

    2012-05-01

    The most frequently reported symptom of exposure to high altitude is loss of body mass and decreased performance which has been attributed to altered protein metabolism affecting skeletal muscles mass. The present study explores the mechanism of chronic hypobaric hypoxia mediated skeletal muscle wasting by evaluating changes in protein turnover and various proteolytic pathways. Male Sprague-Dawley rats weighing about 200 g were exposed to hypobaric hypoxia (7,620 m) for different durations of exposure. Physical performance of rats was measured by treadmill running experiments. Protein synthesis, protein degradation rates were determined by (14)C-Leucine incorporation and tyrosine release, respectively. Chymotrypsin-like enzyme activity of the ubiquitin-proteasome pathway and calpains were studied fluorimetrically as well as using western blots. Declined physical performance by more than 20%, in terms of time taken in exhaustion on treadmill, following chronic hypobaric hypoxia was observed. Compared to 1.5-fold increase in protein synthesis, the increase in protein degradation was much higher (five-folds), which consequently resulted in skeletal muscle mass loss. Myofibrillar protein level declined from 46.79 ± 1.49 mg/g tissue at sea level to 37.36 ± 1.153 (P calpains (three-fold) has been found to be important factors for the enhanced protein degradation rate. The study provided strong evidences suggesting that elevated protein turnover rate lead to skeletal muscle atrophy under chronic hypobaric hypoxia via ubiquitin-proteasome pathway and calpains.

  15. Evidence Report: Risk of Hypobaric Hypoxia from the Exploration Atmosphere

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    Norcross, Jason R.; Conkin, Johnny; Wessel, James H., III; Norsk, Peter; Law, Jennifer; Arias, Diana; Goodwin, Tom; Crucian, Brian; Whitmire, Alexandra; Bloomberg, Jacob; Platts, Steve; Ploutz-Snyder, Lori; Douglas, Grace

    2015-01-01

    Extravehicular activity (EVA) is at the core of a manned space exploration program. Some elements of exploration may be safely and effectively performed by robots, but certain critical elements will require the trained, assertive, and reasoning mind of a human crewmember. To effectively use these skills, NASA needs a safe, effective, and efficient EVA component integrated into the human exploration program. The EVA preparation time should be minimized and the suit pressure should be low to accommodate EVA tasks without causing undue fatigue, physical discomfort, or suit-related trauma. Commissioned in 2005, the Exploration Atmospheres Working Group (EAWG) had the primary goal of recommending to NASA an internal environment that allowed efficient and repetitive EVAs for missions that were to be enabled by the former Constellation Program. At the conclusion of the EAWG meeting, the 8.0 psia and 32% oxygen (O2) environment were recommended for EVA-intensive phases of missions. After re-evaluation in 2012, the 8/32 environment was altered to 8.2 psia and 34% O2 to reduce the hypoxic stress to a crewmember. These two small changes increase alveolar O2 pressure by 11 mmHg, which is expected to significantly benefit crewmembers. The 8.2/34 environment (inspired O2 pressure = 128 mmHg) is also physiologically equivalent to the staged decompression atmosphere of 10.2 psia / 26.5% O2 (inspired O2 pressure = 127 mmHg) used on 34 different shuttle missions for approximately a week each flight. As a result of selecting this internal environment, NASA gains the capability for efficient EVA with low risk of decompression sickness (DCS), but not without incurring the additional negative stimulus of hypobaric hypoxia to the already physiologically challenging spaceflight environment. This report provides a review of the human health and performance risks associated with the use of the 8.2 psia / 34% O2 environment during spaceflight. Of most concern are the potential effects on the

  16. Effect of acute exposure to moderate altitude on muscle power: hypobaric hypoxia vs. normobaric hypoxia.

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    Feriche, Belén; García-Ramos, Amador; Calderón-Soto, Carmen; Drobnic, Franchek; Bonitch-Góngora, Juan G; Galilea, Pedro A; Riera, Joan; Padial, Paulino

    2014-01-01

    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 (Ppress.

  17. [Endogenous ethanol in the blood and tissues of rats with hypobaric hypoxia].

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    Tarasov, Iu A; Ostrovskiĭ, Iu M; Satanovskaia, V I; Liopo, A V; Velichko, M G; Abakumov, G Z

    1989-01-01

    Albino male rats weighing 160-180 g were used to study the effect of short-term hypobaric hypoxia (ascent in an altitude chamber to 2500 m and 5000 m for 1 hr) on endogenous ethanol measured in blood, brain and liver; simultaneously enzymes responsible for ethanol and acetaldehyde metabolism were determined. Endogenous ethanol in blood and tissues was found to be a very sensitive marker of hypoxia which was not correlated with lactate, pyruvate, lipid peroxidation or 11-hydroxycorticosteroids. The latter parameters varied in response to severe hypoxia.

  18. Hypobaric-hypoxia-induced pulmonary damage in rats ameliorated by antioxidant erdosteine.

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    Uzun, Ozge; Balbay, Oner; Comunoğlu, Nil Ustündağ; Yavuz, Ozlem; Nihat Annakkaya, Ali; Güler, Selver; Silan, Coşkun; Erbaş, Mete; Arbak, Peri

    2006-01-01

    Free radical-mediated injury to lung and pulmonary vasculature is an important mechanism in hypoxia-induced lung damage. In this study, we aimed to investigate the potential protective effects of erdosteine as an antioxidant agent on hypobaric hypoxia-induced pulmonary hypertension. Adult male rats were assigned randomly to three groups. The first group of rats was exposed to hypobaric-hypoxia and the second group was treated with erdosteine (20mg/kg, daily) for 2 weeks, during which time they were in a hypoxic chamber. These groups were compared with normoxic controls. All rats were sacrificed after 2 weeks. The hypoxia-induced increase in right ventricle to left ventricle plus septum weight ratio (from 0.20+/-0.01 to 0.26+/-0.01) was reduced significantly in the erdosteine-treated group (0.23+/-0.01). Malondialdehyde levels were elevated (from 0.33+/-0.11 to 0.59+/-0.02) and total antioxidant status was not changed significantly (from 1.77+/-0.42 to 2.61+/-0.23) by hypoxia. In contrast to the hypoxia-exposed group, malondialdehyde levels were significantly decreased in the erdosteine-treated group (0.37+/-0.02). Total antioxidant status (4.03+/-0.22) was significantly higher in erdosteine-treated rats when compared to non-treated rats. Histopathological examination demonstrated that erdosteine prevented inflammation and protected lung parenchyma and pulmonary endothelium of hypoxia-exposed rats.

  19. Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats

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    Zhao, Ming; Huang, Xin; Cheng, Xiang; Lin, Xiao; Zhao, Tong; Wu, Liying; Yu, Xiaodan; Wu, Kuiwu; Fan, Ming

    2017-01-01

    Exposure to hypobaric hypoxia causes neuron cell damage, resulting in impaired cognitive function. Effective interventions to antagonize hypobaric hypoxia-induced memory impairment are in urgent need. Ketogenic diet (KD) has been successfully used to treat drug-resistant epilepsy and improves cognitive behaviors in epilepsy patients and other pathophysiological animal models. In the present study, we aimed to explore the potential beneficial effects of a KD on memory impairment caused by hypobaric hypoxia and the underlying possible mechanisms. We showed that the KD recipe used was ketogenic and increased plasma levels of ketone bodies, especially β-hydroxybutyrate. The results of the behavior tests showed that the KD did not affect general locomotor activity but obviously promoted spatial learning. Moreover, the KD significantly improved the spatial memory impairment caused by hypobaric hypoxia (simulated altitude of 6000 m, 24 h). In addition, the improving-effect of KD was mimicked by intraperitoneal injection of BHB. The western blot and immunohistochemistry results showed that KD treatment not only increased the acetylated levels of histone H3 and histone H4 compared to that of the control group but also antagonized the decrease in the acetylated histone H3 and H4 when exposed to hypobaric hypoxia. Furthermore, KD-hypoxia treatment also promoted PKA/CREB activation and BDNF protein expression compared to the effects of hypoxia alone. These results demonstrated that KD is a promising strategy to improve spatial memory impairment caused by hypobaric hypoxia, in which increased modification of histone acetylation plays an important role. PMID:28355243

  20. Intermittent hypoxia hypobaric exposure minimized oxidative stress and antioxidants in brain cells of Sprague Dawleymice

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    Wardaya Wardaya

    2013-05-01

    Full Text Available AbstrakLatar belakang: Hipoksia hypobaric meningkatkan produksi radikal bebas, terutama spesies oksigen reaktif (ROS. Peningkatan ROS akan menyebabkan stres oksidatif bila tidak disertai dengan peningkatan enzim antioksidan. Kondisi ini dapat dikurangi dengan hipoksia hipobarik intermiten (HHI. Tujuan penelitian ini mengidentifikasi frekuensi IHH yang dapat meminimalkan efek hipoksia hipobarik terhadap stres oksidatif dan aktivitas antioksidan spesifik pada tikus Sprague Dawley.Metode: Penelitian eksperimental pada bulan Februari-April 2010, Subjek terdiri dari satu kelompok kontrol dan empat kelompok paparan pada mencit jantan Sprague Dawley. Setiap kelompok terdiri dari 5 tikus. Kelompok kontrol tidak terpapar IHH. Kelompok terpapar (dengan selang waktu satu minggu terpapar sekali, dua kali, tiga kali, atau empat kali IHH. Semua kelompok paparan dipaparkan hipobarik setara dengan ketinggian: 35.000 ft (1 menit, 25.000 ft (5 menit, dan 18.000 ft (25 menit. Jaringan otak diperiksa untuk 8-OHdG dan SOD.Hasil:Setelah tiga paparan IHH tingkat 8-OHdG sudah kembali ke nilai kontrol (P = 0,843. Tingkat SOD meningkat secara progresif pada dua, tiga, dan empat kali paparan IHH. Bahkan setelah paparan kedua, tingkat SOD sudah sama dengan nilai kontrol, 0,231 ± 0,042 (P = 0,191.Kesimpulan: Tiga kali IHH sudah dapat meminimalkan pengaruh hipoksia hipobarik terhadap stres oksidatif dan aktivitas spesifik antioksidan pada tikus Sprague Dawley.Kata kunci: hipoksia hipobarik intermiten, stres oksidatif, antioksidanAbstractBackground: Hypoxia hypobaric increase the production of free radicals, especially reactive oxygen species (ROS. The increase in ROS would cause oxidative stress when not accompanied by an increase in antioxidant enzymes. This condition may minimize by intermittent hypobaric hypoxia (IHH. This study aimed to identify the number of IHH which may minimize the effect of hypoxia hypobaric on oxidative stress and the specific activity of

  1. Exogenous sphingosine-1-phosphate boosts acclimatization in rats exposed to acute hypobaric hypoxia: assessment of haematological and metabolic effects.

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    Sonam Chawla

    Full Text Available BACKGROUND: The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P to improve acclimatization to simulated hypobaric hypoxia. EXPERIMENTAL APPROACH: Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620 m for 6 hours following S1P pre-treatment for three days. MAJOR FINDINGS: Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. CONCLUSION: The study findings highlight S1P's merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes.

  2. Exogenous Sphingosine-1-Phosphate Boosts Acclimatization in Rats Exposed to Acute Hypobaric Hypoxia: Assessment of Haematological and Metabolic Effects

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    Chawla, Sonam; Rahar, Babita; Singh, Mrinalini; Bansal, Anju; Saraswat, Deepika; Saxena, Shweta

    2014-01-01

    Background The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia. Experimental Approach Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620m for 6 hours) following S1P pre-treatment for three days. Major Findings Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. Conclusion The study findings highlight S1P’s merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes. PMID:24887065

  3. The hypobaric hypoxia affects the oxidant balance in skeletal muscle regeneration of women

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    Rosa Mancinelli

    2016-07-01

    Full Text Available Aim: The aim of this study was to determine whether a 14-day trekking expeditions, in high altitude hypoxic environment, triggers redox disturbance at the level of satellite cells (adult stem cells in young women.Methods: We collected muscle biopsies from Vastus Lateralis muscle for both single fiber analysis and satellite cells isolation. The samples collected before (PRE-Hypoxia and after (POST-Hypoxia the trekking in the Himalayas were compared. Satellite cells were investigated for oxidative stress (oxidant production, antioxidant enzyme activity and lipid damage, mitochondrial potential variation, gene profile of HIF and myogenic transcription factors (Pax7, MyoD, myogenin and miRNA expression (miR-1, miR-133, miR-206.Results: The nuclear domain analysis showed a significant fusion and consequent reduction of the Pax7+ satellite cells in the single mature fibers. The POST-Hypoxia myoblasts obtained by two out of six volunteers showed high superoxide anion production and lipid peroxidation along with impaired dismutase and catalase and mitochondrial potential. The transcription profile and miRNA expression were different for oxidized and non oxidized cells.Conclusions: The present study supports the phenomenon of hypobaric-hypoxia-induced oxidative stress and its role in the impairment of the regenerative capacity of satellite cells derived from the Vastus Lateralis muscle of young adult female subjects.

  4. Regional differences in the cerebral blood flow velocity response to hypobaric hypoxia at high altitudes.

    Science.gov (United States)

    Feddersen, Berend; Neupane, Pritam; Thanbichler, Florian; Hadolt, Irmgard; Sattelmeyer, Vera; Pfefferkorn, Thomas; Waanders, Robb; Noachtar, Soheyl; Ausserer, Harald

    2015-11-01

    Symptoms of acute mountain sickness (AMS) may appear above 2,500 m altitude, if the time allowed for acclimatization is insufficient. As the mechanisms underlying brain adaptation to the hypobaric hypoxic environment are not fully understood, a prospective study was performed investigating neurophysiological changes by means of near infrared spectroscopy, electroencephalograpy (EEG), and transcranial doppler sonography at 100, 3,440 and 5,050 m above sea level in the Khumbu Himal, Nepal. Fourteen of the 26 mountaineers reaching 5,050 m altitude developed symptoms of AMS between 3,440 and 5,050 m altitude (Lake-Louise Score ⩾3). Their EEG frontal beta activity and occipital alpha activity increased between 100 and 3,440 m altitude, i.e., before symptoms appeared. Cerebral blood flow velocity (CBFV) in the anterior and middle cerebral arteries (MCAs) increased in all mountaineers between 100 and 3,440 m altitude. During further ascent to 5,050 altitude, mountaineers with AMS developed a further increase in CBFV in the MCA, whereas in all mountaineers CBFV decreased continuously with increasing altitude in the posterior cerebral arteries. These results indicate that hypobaric hypoxia causes different regional changes in CBFV despite similar electrophysiological changes.

  5. Muscle fatigue and exhaustion during dynamic leg exercise in normoxia and hypobaric hypoxia

    DEFF Research Database (Denmark)

    Fulco, C S; Lewis, S F; Frykman, Peter

    1996-01-01

    Using an exercise device that integrates maximal voluntary static contraction (MVC) of knee extensor muscles with dynamic knee extension, we compared progressive muscle fatigue, i.e., rate of decline in force-generating capacity, in normoxia (758 Torr) and hypobaric hypoxia (464 Torr). Eight...... healthy men performed exhaustive constant work rate knee extension (21 +/- 3 W, 79 +/- 2 and 87 +/- 2% of 1-leg knee extension O2 peak uptake for normoxia and hypobaria, respectively) from knee angles of 90-150 degrees at a rate of 1 Hz. MVC (90 degrees knee angle) was performed before dynamic exercise...... and during MVC force was 578 +/- 29 N in normoxia and 569 +/- 29 N in hypobaria before exercise and fell, at exhaustion, to similar levels (265 +/- 10 and 284 +/- 20 N for normoxia and hypobaria, respectively; P > 0.05) that were higher (P

  6. Ω3 Supplementation and Intermittent Hypobaric Hypoxia Induce Cardioprotection Enhancing Antioxidant Mechanisms in Adult Rats

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    Emilio A. Herrera

    2015-02-01

    Full Text Available Intermittent hypobaric hypoxia (IH is linked with oxidative stress, impairing cardiac function. However, early IH also activate cardio-protective mechanisms. Omega 3 fatty acids (Ω3 induce cardioprotection by reducing infarct size and reinforcing antioxidant defenses. The aim of this work was to determine the combined effects of IH and Ω3 on cardiac function; oxidative balance and inflammatory state. Twenty-eight rats were randomly divided into four groups: normobaric normoxia (N; N + Ω3 (0.3 g·kg−1·day−1; IH; and IH + Ω3. IH was induced by 4 intercalate periods of hypoxia (4 days—normoxia (4 days in a hypobaric chamber during 32 days. At the end of the exposure, hearts were mounted in a Langendorff system and subjected to 30 min of ischemia followed by 120 min of reperfusion. In addition, we determined HIF-1α and ATP levels, as well as oxidative stress by malondialdehyde and nitrotyrosine quantification. Further, the expression of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase was determined. NF-kappaB and myeloperoxidase levels were assessed in the hearts. Relative to N hearts, IH improved left ventricular function (Left ventricular developed pressure: N; 21.8 ± 3.4 vs. IH; 42.8 ± 7.1 mmHg; p < 0.05; reduced oxidative stress (Malondialdehyde: N; 14.4 ± 1.8 vs. IH; 7.3 ± 2.1 μmol/mg prot.; p < 0.05; and increased antioxidant enzymes expression. Supplementation with Ω3 induces similar responses as IH group. Our findings suggest that both, IH and Ω3 in an independent manner, induce functional improvement by antioxidant and anti-inflammatory mechanisms, establishing cardio-protection.

  7. The influence of intermittent hypobaric hypoxia on the brain iron metabolism in adult Sprague dawley rats

    Institute of Scientific and Technical Information of China (English)

    Wu Qiong; Li Yaru; Chang Yanzhong

    2015-01-01

    Objective:Iron is an essential element in all living organisms and is required as a cofactor for oxygen-binding proteins. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly inter-connected. In mammalian cells, exposure to a low-oxygen environment triggers a hypoxic response pathway cen-tered on the regulated expression of the hypoxia-inducible transcription factor ( HIF) . Hypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis. However, little is known about brain iron metabolism after intermittent hypobaric hypoxia ( IHH) treatment. In this study, adult Sprague dawley ( SD) rats were treated with IHH for 28 days, 8h per day and then we detected iron homeostasis in different brain areas of SD rats. Results:The protein level of hippocampus transferrin receptor 1 ( TfR1 ) , divalent metal transporter 1 (DMT1) with IRE, DMT1 (-IRE), ferritin-H, iron regulatory protein (IRP) 2 and ceruloplasmin (CP) is ele-vated significantly while ferritin-L decreased. We have also found the down regulation of IRP1. We observe the same results in the cerebral cortex in the brain. Conclusions:We first discover that IHH has an influence on the brain iron homeostasis and the decreased ferritin-L corresponds to the down regulation of IRP1 indicating hypoxia can affect the expression of ferritin-L through IRE/IRP system. Although there is a marked increase in TfR1 ex-pression that would lead to the raised level of LIP in cells. It can finally result in the higher ROS which can damage the cells. The concerned mechanisms involved in it remain to be deliberated.

  8. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats.

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    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.

  9. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not in males.

    Science.gov (United States)

    Kanekar, Shami; Bogdanova, Olena V; Olson, Paul R; Sung, Young-Hoon; D'Anci, Kristen E; Renshaw, Perry F

    2015-03-01

    Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression-like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males.

  10. High Resolution ECG for Evaluation of Heart Function During Exposure to Subacute Hypobaric Hypoxia

    Science.gov (United States)

    Zupet, Petra; Finderle, Zarko; Schlegel, Todd T.; Princi, Tanja; Starc, Vito

    2010-01-01

    High altitude climbing presents a wide spectrum of health risks, including exposure to hypobaric hypoxia. Risks are also typically exacerbated by the difficulty in appropriately monitoring for early signs of organ dysfunction in remote areas. We investigated whether high resolution advanced ECG analysis might be helpful as a non-invasive and easy-to-use tool (e.g., instead of Doppler echocardiography) for evaluating early signs of heart overload in hypobaric hypoxia. Nine non-acclimatized healthy trained alpine rescuers (age 43.7 plus or minus 7.3 years) climbed in four days to the altitude of 4,200 m on Mount Ararat. Five-minute high-resolution 12-lead electrocardiograms (ECGs) were recorded (Cardiosoft) in each subject at rest in the supine position on different days but at the same time of day at four different altitudes: 400 m (reference altitude), 1,700 m, 3,200 m and 4,200 m. Changes in conventional and advanced resting ECG parameters, including in beat-to-beat QT and RR variability, waveform complexity, signal-averaged, high-frequency and spatial/spatiotemporal ECG was estimated by calculation of the regression coefficients in independent linear regression models. A p-value of less than 0.05 was adopted as statistically significant. As expected, the RR interval and its variability both decreased with increasing altitude, with trends k = -96 ms/1000 m with p = 0.000 and k = -9 ms/1000 m with p = 0.001, respectively. Significant changes were found in P-wave amplitude, which nearly doubled from the lowest to the highest altitude (k = 41.6 microvolt/1000 m with p = 0.000), and nearly significant changes in P-wave duration (k = 2.9 ms/1000 m with p = 0.059). Changes were less significant or non-significant in other studied parameters including those of waveform complexity, signal-averaged, high-frequency and spatial/spatiotemporal ECG. High resolution ECG analysis, particularly of the P wave, shows promise as a tool for monitoring early changes in heart function

  11. Effects of hypobaric hypoxia on adenine nucleotide pools, adenine nucleotide transporter activity and protein expression in rat liver

    Institute of Scientific and Technical Information of China (English)

    Cong-Yang Li; Jun-Ze Liu; Li-Ping Wu; Bing Li; Li-Fen Chen

    2006-01-01

    AIM: To explore the effect of hypobaric hypoxia on mitochondrial energy metabolism in rat liver.METHODS: Adult male Wistar rats were exposed to a hypobaric chamber simulating 5000 m high altitude for 23 h every day for 0 (HO), 1 (H1), 5 (HS), 15 (H15) and 30 d (H30) respectively. Rats were sacrificed by decapitation and liver was removed. Liver mitochondria were isolated by differential centrifugation program. The size of adenine nucleotide pool (ATP, ADP, and AMP) in tissue and mitochondria was separated and measured by high performance liquid chromatography (HPLC). The adenine nucleotide transporter (ANT) activity was determined by isotopic technique. The ANT total protein level was determined by Western blot. RESULTS: Compared with HO group, intra-mitochondrial ATP content decreased in all hypoxia groups. However,the H5 group reached the lowest point (70.6%) (P< 0.01)when compared to the control group. Intra-mitochondrial ADP and AMP level showed similar change in all hypoxia groups and were significantly lower than that in HO group. In addition, extra-mitochondrial ATP and ADP content decreased significantly in all hypoxia groups.Furthermore, extra-mitochondrial AMP in groups H5, H15and H30 was significantly lower than that in HO group,whereas H1 group had no marked change compared to the control situation. The activity of ANT in hypoxia groups decreased significantly, which was the lowest in H5 group (55.7%) (P<0.01) when compared to HO group. ANT activity in H30 group was higher than in H15 group, but still lower than that in HO group. ANT protein level in H5, H15, H30 groups, compared with HO group decreased significantly, which in H5 group was the lowest, being 27.1% of that in HO group (P<0.01). ANT protein level in H30 group was higher than in H15 group,but still lower than in HO group.CONCLUSION: Hypobaric hypoxia decreases the mitochondrial ATP content in rat liver, while mitochondrial ATP level recovers during long-term hypoxia exposure.The lower

  12. Revisiting cobalt chloride preconditioning to prevent hypobaric hypoxia-induced damage: identification of global proteomic alteration and key networks.

    Science.gov (United States)

    Ahmad, Yasmin; Mishra, Shalini; Arya, Adtiya; Paul, Subhojit; Sharma, Manish; Prasad, Jyotsna; Bhargava, Kalpana

    2016-05-01

    Several studies have supported the hypoxia mimetic roles and cytoprotective properties of cobalt chloride in vitro and in vivo. However, a clear understanding of biological process-based mechanism that integrates the available information remains unknown. This study was aimed to explore the potential mechanism of cobalt chloride deciphering its benefits and well-known physiological challenge caused by hypobaric hypoxia that reportedly affects nearly 24 % of the global population. In order to explore the mechanism of CoCl2, we used global proteomic and systems biology approach in rat model to provide a deeper insight into molecular mechanisms of preconditioning. Furthermore, key conclusions were drawn based on biological network analysis and their enrichment with ontological overlaps. The study was further strengthened by consistent identification of validation of proteins using immunoblotting. CoCl2-pretreated animals exposed to hypoxia showed two significant networks, one lipid metabolism and other cell cycle associated, with a total score of 23 and eight focus molecules. In this study, we delineated two primary routes: one, by direct modulation of reactive oxygen species metabolism and, second, by regulation of lipid metabolism which was not known until now. The previously known benefits of cobalt chloride during physiological challenge by hypobaric hypoxia are convincing and could be explained by some basic set of metabolic and molecular reorganization within the hypoxia model. Interestingly, we also observed some of the completely unknown roles of cobalt chloride such as regulation of lipid that could undulate the translational roles of cobalt chloride supplementation beyond hypoxia preconditioning.

  13. Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats

    Science.gov (United States)

    Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

    2014-02-01

    Hypobaric hypoxia (HH) induces oxidative stress (OS) and is associated with the generation of reactive oxygen species (ROS). Vitamin C is an efficient antioxidant, and it is used in a high-altitude environment to reduce the OS. The present study explores the role of vitamin C on some HH-induced changes of immune parameters in rats which were exposed to HHc condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days with and without vitamin C administration at three different doses (200, 400, and 600 mg/kg body wt). The phagocytic activity of circulating blood WBC was increased, and the cytotoxic activity of splenic mononuclear cell (MNC) and the delayed type of hypersensitivity (DTH) responses to bovine serum albumin (BSA) were decreased in rats exposed to HHc condition, but these immune changes were blocked after administration of vitamin C at 400 mg/kg body wt. The leukocyte adhesive inhibition index (LAI) was not altered either in HHc condition or after administration of vitamin C in HHc condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HHc condition which was blocked after administration of vitamin C (400 mg/kg body wt). The immune parameters and serum CORT concentration, however, did not show any recovery after administration of vitamin C at the dose of 200 and 600 mg/kg body wt. The present study indicates that administration of vitamin C at a dose of 400 mg/kg body wt may prevent the HH-induced immunological changes but not at the lower dose (200 mg/kg body wt) or higher dose (600 mg/kg body wt) in rats.

  14. Comparison of "Live High-Train Low" in normobaric versus hypobaric hypoxia.

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    Jonas J Saugy

    Full Text Available We investigated the changes in both performance and selected physiological parameters following a Live High-Train Low (LHTL altitude camp in either normobaric hypoxia (NH or hypobaric hypoxia (HH replicating current "real" practices of endurance athletes. Well-trained triathletes were split into two groups (NH, n = 14 and HH, n = 13 and completed an 18-d LHTL camp during which they trained at 1100-1200 m and resided at an altitude of 2250 m (PiO2  = 121.7±1.2 vs. 121.4±0.9 mmHg under either NH (hypoxic chamber; FiO2 15.8±0.8% or HH (real altitude; barometric pressure 580±23 mmHg conditions. Oxygen saturations (SpO2 were recorded continuously daily overnight. PiO2 and training loads were matched daily. Before (Pre- and 1 day after (Post- LHTL, blood samples, VO2max, and total haemoglobin mass (Hb(mass were measured. A 3-km running test was performed near sea level twice before, and 1, 7, and 21 days following LHTL. During LHTL, hypoxic exposure was lower for the NH group than for the HH group (220 vs. 300 h; P<0.001. Night SpO2 was higher (92.1±0.3 vs. 90.9±0.3%, P<0.001, and breathing frequency was lower in the NH group compared with the HH group (13.9±2.1 vs. 15.5±1.5 breath.min(-1, P<0.05. Immediately following LHTL, similar increases in VO2max (6.1±6.8 vs. 5.2±4.8% and Hb(mass (2.6±1.9 vs. 3.4±2.1% were observed in NH and HH groups, respectively, while 3-km performance was not improved. However, 21 days following the LHTL intervention, 3-km run time was significantly faster in the HH (3.3±3.6%; P<0.05 versus the NH (1.2±2.9%; ns group. In conclusion, the greater degree of race performance enhancement by day 21 after an 18-d LHTL camp in the HH group was likely induced by a larger hypoxic dose. However, one cannot rule out other factors including differences in sleeping desaturations and breathing patterns, thus suggesting higher hypoxic stimuli in the HH group.

  15. Same performance changes after Live High-Train Low in normobaric versus hypobaric hypoxia

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    Jonas J. Saugy

    2016-04-01

    Full Text Available Purpose: We investigated the changes in physiological and performance parameters after a Live High-Train Low (LHTL altitude camp in normobaric (NH or hypobaric hypoxia (HH to reproduce the actual training practices of endurance athletes using a crossover-designed study. Methods: Well-trained triathletes (n=16 were split into two groups and completed two 18-day LTHL camps during which they trained at 1100-1200 m and lived at 2250 m (PiO2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg under NH (hypoxic chamber; FiO2 18.05 ± 0.03% or HH (real altitude; barometric pressure 580.2 ± 2.9 mmHg conditions. The subjects completed the NH and HH camps with a one-year washout period. Measurements and protocol were identical for both phases of the crossover study. Oxygen saturation (SpO2 was constantly recorded nightly. PiO2 and training loads were matched daily. Blood samples and VO2max were measured before (Pre- and 1 day after (Post-1 LHTL. A 3-km running-test was performed near sea level before and 1, 7, and 21 days after training camps. Results: Total hypoxic exposure was lower for NH than for HH during LHTL (230 vs. 310 h; P<0.001. Nocturnal SpO2 was higher in NH than in HH (92.4 ± 1.2 vs. 91.3 ± 1.0%, P<0.001. VO2max increased to the same extent for NH and HH (4.9 ± 5.6 vs. 3.2 ± 5.1%. No difference was found in hematological parameters. The 3-km run time was significantly faster in both conditions 21 days after LHTL (4.5 ± 5.0 vs. 6.2 ± 6.4% for NH and HH, and no difference between conditions was found at any time. Conclusion: Increases in VO2max and performance enhancement were similar between NH and HH conditions.

  16. Chronic intermittent hypobaric hypoxia protects the heart against ischemia/reperfusion injury through upregulation of antioxidant enzymes in adult guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Hui-cai GUO; Zhe ZHANG; Li-nan ZHANG; Chen XIONG; Chen FENG; Qian LIU; Xu LIU; Xiao-lu SHI; Yong-li WANG

    2009-01-01

    Aim:To investigate the protection and the anti-oxidative mechanism afforded by chronic intermittent hypobaric hypoxia (CIHH) against ischemia/reperfusion (I/R) injury in guinea pig hearts.Methods:Adult male guinea pigs were exposed to CIHH by mimicking a 5000 m high altitude (pB=404 mmHg,p02=84 mmHg) in a hypobaric chamber for 6 h/day for 28 days.Langendorff-perfused isolated guinea pig hearts were used to measure variables of left ventricular function during baseline perfusion,ischemia and the reperfusion period.The activity and protein expression of antioxidant enzymes in the left myocardium were evaluated using biochemical methods and Western blotting.respectively.Intracellular reactive oxygen species (ROS) were assessed using ROS-sensitive fluorescence.Results:After 30 min of global no-flow ischemia followed by 60 min of reperfusion,myocardial function had better recovery rates in CIHH guinea pig hearts than in control hearts.The activity and protein expression of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of CIHH guinea pigs.Pretreatment of control hearts with an antioxidant mixture containing SOD and CAT exerted cardioprotective effects similar to CIHH.The irreversible CAT inhibitor aminotriazole (ATZ) abolished the cardioprotection of CIHH.Cardiac contractile dysfunction and oxidative stress induced by exogenous hydrogen peroxide (H2O2) were attenuated by CIHH and CAT.Conclusions:These data suggest that CIHH protects the heart against I/R injury through upregulation of antioxidant enzymes in guinea pig.

  17. Proteins modulation in human skeletal muscle in the early phase of adaptation to hypobaric hypoxia

    DEFF Research Database (Denmark)

    Vigano, A.; Ripamonti, M.; Palma, S. De;

    2008-01-01

    High altitude hypoxia is a paraphysiological condition triggering redox status disturbances of cell organization leading, via oxidative stress, to proteins, lipids, and DNA damage. In man, skeletal muscle, after prolonged exposure to hypoxia, undergoes mass reduction and alterations at the cellul......, whereas the mammalian target of rapamycin (mTOR), a marker of protein synthesis, was reduced Udgivelsesdato: 2008/11...

  18. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Intermittent hypoxia has been shown to provide myocardial protection against ishemia/reperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts compared with normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reduce myocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl

  19. Effect of acute hypobaric hypoxia on the endothelial glycocalyx and digital reactive hyperemia in humans

    DEFF Research Database (Denmark)

    Johansson, Pär I; Bergström, Anita; Aachmann-Andersen, Niels Jacob;

    2014-01-01

    /nitrate decreased from 23 (18-27) μM at baseline to 19 (14-24) μM and 18 (14-21) μM in hypoxia and recovery, respectively (p index, RHI) decreased from 1.80 (1.52-2.07) in normoxia to 1.62 (1.28-1.96) after 2...

  20. Prooxidant/Antioxidant Balance in Hypoxia: A Cross-Over Study on Normobaric vs. Hypobaric "Live High-Train Low".

    Directory of Open Access Journals (Sweden)

    Tadej Debevec

    Full Text Available "Live High-Train Low" (LHTL training can alter oxidative status of athletes. This study compared prooxidant/antioxidant balance responses following two LHTL protocols of the same duration and at the same living altitude of 2250 m in either normobaric (NH or hypobaric (HH hypoxia. Twenty-four well-trained triathletes underwent the following two 18-day LHTL protocols in a cross-over and randomized manner: Living altitude (PIO2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg in NH and HH, respectively; training "natural" altitude (~1000-1100 m and training loads were precisely matched between both LHTL protocols. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP and nitrotyrosine] and antioxidant markers [ferric-reducing antioxidant power (FRAP, superoxide dismutase (SOD and catalase], NO metabolism end-products (NOx and uric acid (UA were determined before (Pre and after (Post the LHTL. Cumulative hypoxic exposure was lower during the NH (229 ± 6 hrs. compared to the HH (310 ± 4 hrs.; P<0.01 protocol. Following the LHTL, the concentration of AOPP decreased (-27%; P<0.01 and nitrotyrosine increased (+67%; P<0.05 in HH only. FRAP was decreased (-27%; P<0.05 after the NH while was SOD and UA were only increased following the HH (SOD: +54%; P<0.01 and UA: +15%; P<0.01. Catalase activity was increased in the NH only (+20%; P<0.05. These data suggest that 18-days of LHTL performed in either NH or HH differentially affect oxidative status of athletes. Higher oxidative stress levels following the HH LHTL might be explained by the higher overall hypoxic dose and different physiological responses between the NH and HH.

  1. Acetylation of histones in neocortex and hippocampus of rats exposed to different modes of hypobaric hypoxia: Implications for brain hypoxic injury and tolerance.

    Science.gov (United States)

    Samoilov, Mikhail; Churilova, Anna; Gluschenko, Tatjana; Vetrovoy, Oleg; Dyuzhikova, Natalia; Rybnikova, Elena

    2016-03-01

    Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180mm Hg, 3h) and neuroprotective preconditioning mode (three episodes of 360mm Hg for 2h spaced at 24h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II-III, V) and hippocampus (CA1, CA3) by 3-24h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24h, whereas acetylation of H3K24 was intense but transient, peaked at 3h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance.

  2. The effects of breathing a helium-oxygen gas mixture on maximal pulmonary ventilation and maximal oxygen consumption during exercise in acute moderate hypobaric hypoxia.

    Science.gov (United States)

    Ogawa, Takeshi; Calbet, Jose A L; Honda, Yasushi; Fujii, Naoto; Nishiyasu, Takeshi

    2010-11-01

    To test the hypothesis that maximal exercise pulmonary ventilation (VE max) is a limiting factor affecting maximal oxygen uptake (VO2 max) in moderate hypobaric hypoxia (H), we examined the effect of breathing a helium-oxygen gas mixture (He-O(2); 20.9% O(2)), which would reduce air density and would be expected to increase VE max. Fourteen healthy young male subjects performed incremental treadmill running tests to exhaustion in normobaric normoxia (N; sea level) and in H (atmospheric pressure equivalent to 2,500 m above sea level). These exercise tests were carried out under three conditions [H with He-O(2), H with normal air and N] in random order. VO2 max and arterial oxy-hemoglobin saturation (SaO(2)) were, respectively, 15.2, 7.5 and 4.0% higher (all p max, 171.9 ± 16.1 vs. 150.1 ± 16.9 L/min; VO2 max, 52.50 ± 9.13 vs. 48.72 ± 5.35 mL/kg/min; arterial oxyhemoglobin saturation (SaO(2)), 79 ± 3 vs. 76 ± 3%). There was a linear relationship between the increment in VE max and the increment in VO2 max in H (r = 0.77; p VO2 max, both groups showed increased VE max and SaO(2) in H with He-O(2), but VO2 max was increased only in the high VO2 max group. These findings suggest that in acute moderate hypobaric hypoxia, air-flow resistance can be a limiting factor affecting VE max; consequently, VO2 max is limited in part by VE max especially in subjects with high VO2 max.

  3. NITRIC OXIDE (NO, CITRULLINE - NO CYCLE ENZYMES, GLUTAMINE SYNTHETASE AND OXIDATIVE STRESS IN ANOXIA (HYPOBARIC HYPOXIA AND REPERFUSION IN RAT BRAIN

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    M. Swamy, Mohd Jamsani Mat Salleh, K. N .S. Sirajudeen, Wan Roslina Wan Yusof, G. Chandran

    2010-01-01

    Full Text Available Nitric oxide is postulated to be involved in the pathophysiology of neurological disorders due to hypoxia/ anoxia in brain due to increased release of glutamate and activation of N-methyl-D-aspartate receptors. Reactive oxygen species have been implicated in pathophysiology of many neurological disorders and in brain function. To understand their role in anoxia (hypobaric hypoxia and reperfusion (reoxygenation, the nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, glutamine synthetase and arginase activities along with the concentration of nitrate /nitrite, thiobarbituric acid reactive substances and total antioxidant status were estimated in cerebral cortex, cerebellum and brain stem of rats subjected to anoxia and reperfusion. The results of this study clearly demonstrated the increased production of nitric oxide by increased activity of nitric oxide synthase. The increased activities of argininosuccinate synthetase and argininosuccinate lyase suggest the increased and effective recycling of citrulline to arginine in anoxia, making nitric oxide production more effective and contributing to its toxic effects. The decreased activity of glutamine synthetase may favor the prolonged availability of glutamic acid causing excitotoxicity leading to neuronal damage in anoxia. The increased formation of thiobarbituric acid reactive substances and decreased total antioxidant status indicate the presence of oxidative stress in anoxia and reperfusion. The increased arginase and sustained decrease of GS activity in reperfusion group likely to be protective.

  4. Cardiovascular function in term fetal sheep conceived, gestated and studied in the hypobaric hypoxia of the Andean altiplano.

    Science.gov (United States)

    Herrera, Emilio A; Rojas, Rodrigo T; Krause, Bernardo J; Ebensperger, Germán; Reyes, Roberto V; Giussani, Dino A; Parer, Julian T; Llanos, Aníbal J

    2016-03-01

    High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. However, adult humans and animals that have evolved at altitude show certain protection against the effects of chronic hypoxia. Whether the highland fetus shows similar protection against high altitude gestation is unclear. We tested the hypothesis that high-altitude fetal sheep have evolved cardiovascular compensatory mechanisms to withstand chronic hypoxia that are different from lowland sheep. We studied seven high-altitude (HA; 3600 m) and eight low-altitude (LA; 520 m) pregnant sheep at ∼90% gestation. Pregnant ewes and fetuses were instrumented for cardiovascular investigation. A three-period experimental protocol was performed in vivo: 30 min of basal, 1 h of acute superimposed hypoxia (∼10% O2) and 30 min of recovery. Further, we determined ex vivo fetal cerebral and femoral arterial function. HA pregnancy led to chronic fetal hypoxia, growth restriction and altered cardiovascular function. During acute superimposed hypoxia, LA fetuses redistributed blood flow favouring the brain, heart and adrenals, whereas HA fetuses showed a blunted cardiovascular response. Importantly, HA fetuses have a marked reduction in umbilical blood flow versus LA. Isolated cerebral arteries from HA fetuses showed a higher contractile capacity but a diminished response to catecholamines. In contrast, femoral arteries from HA fetuses showed decreased contractile capacity and increased adrenergic contractility. The blunting of the cardiovascular responses to hypoxia in fetuses raised in the Alto Andino may indicate a change in control strategy triggered by chronic hypoxia, switching towards compensatory mechanisms that are more cost-effective in terms of oxygen uptake.

  5. Effects of prolonged exposure to hypobaric hypoxia on oxidative stress, inflammation and gluco-insular regulation: the not-so-sweet price for good regulation.

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    Mario Siervo

    Full Text Available OBJECTIVES: The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses. METHODS: After baseline testing in London (75 m, 24 subjects ascended from Kathmandu (1,300 m to Everest Base Camp (EBC;5,300 m over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m. Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR] along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE, inflammation (Interleukin-6 [IL-6] and counter-regulatory hormones (glucagon, adrenalin, noradrenalin. In addition, peripheral oxygen saturation (SpO2 and venous blood lactate concentrations were determined. RESULTS: SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE and inflammation (IL-6. Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight. CONCLUSIONS: Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.

  6. AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.

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    Andrew W Subudhi

    Full Text Available An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1 to describe a phenotype for successful acclimatization and assess its retention and 2 use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS, cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14 or 21 (n = 7 days at 1525 m. At 16 days at 5260 m we observed: 1 increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 9±4 mmHg to 45±4 while PaCO2 dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2 no AMS; 3 improved cognitive function; and 4 improved exercise performance by 8±8% (all changes p<0.01. Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.

  7. Design and conduct of Xtreme Everest 2: An observational cohort study of Sherpa and lowlander responses to graduated hypobaric hypoxia [v1; ref status: indexed, http://f1000r.es/57m

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    Edward Gilbert-Kawai

    2015-04-01

    Full Text Available Objective: Oxygen availability falls with ascent to altitude and also as a consequence of critical illness. Because cellular sequelae and adaptive processes may be shared in both circumstances, high altitude exposure (‘physiological hypoxia’ assists in the exploration of the response to pathological hypoxia. We therefore studied the response of healthy participants to progressive hypobaric hypoxia at altitude. The primary objective of the study was to identify differences between high altitude inhabitants (Sherpas and lowland comparators. Methods: We performed an observational cohort study of human responses to progressive hypobaric hypoxia (during ascent and subsequent normoxia (following descent comparing Sherpas with lowlanders. Studies were conducted in London (35m, Kathmandu (1300m, Namche Bazaar (3500m and Everest Base Camp (5300m. Of 180 healthy volunteers departing from Kathmandu, 64 were Sherpas and 116 were lowlanders. Physiological, biochemical, genetic and epigenetic data were collected. Core studies focused on nitric oxide metabolism, microcirculatory blood flow and exercise performance. Additional studies performed in nested subgroups examined mitochondrial and metabolic function, and ventilatory and cardiac variables. Of the 180 healthy participants who left Kathmandu, 178 (99% completed the planned trek. Overall, more than 90% of planned testing was completed. Forty-four study protocols were successfully completed at altitudes up to and including 5300m. A subgroup of identical twins (all lowlanders was also studied in detail. Conclusion: This programme of study (Xtreme Everest 2 will provide a rich dataset relating to human adaptation to hypoxia, and the responses seen on re-exposure to normoxia. It is the largest comprehensive high altitude study of Sherpas yet performed. Translational data generated from this study will be of relevance to diseases in which oxygenation is a major factor.

  8. 低压氧舱慢性间断性缺氧诱导大鼠膈神经长时程易化%Phrenic long-term facilitation induced by hypobaric chronic intermittent hypoxia in rats

    Institute of Scientific and Technical Information of China (English)

    陈阳; 刘津平; 魏晓燕; 赵彩红; 李柱一; 刘莹莹

    2011-01-01

    Objective: Long-term facilitation (LTF) is an important electrophysiological characteristic indicative of respiratory neuroplasticity, and is tightly related to sleep disorders. Phrenic LTF can be induced by acute intermittent hypoxia (AIH, 3-5 episodic hypoxia), whereas chronic intermittent hypoxia (CIH) lasting for over one week leads to a large enhanced phrenic LTF. CIH rat models is usually prepared with alternately 5 min of 10% O2 + 90% N2, and 5 min of normoxia for 12 h/d for at least 7 d, a process that needs large amount of mixed gases, and is expensive. We aimed to establish an enhanced phrenic LTF model in intact rats in precondition with hypobaric chronic episodic hypoxia. Methods: Adult Sprague-Dawley rats were housed in a chamber and maintained with alternately 5 min of hypobaric hypoxia and 5 min of normoxia for 12 h/d for 7 consecutive days. Hypobaric hypoxia was achieved by air evacuation to gradually reach a pressure of 210-220 mmHg, corresponding to an altitude of around 9000 m. On the eighth day, both CIH and control animals were treated with AIH, to induce phrenic LTF expression. The control animals received AIH challenge only. Alterations of phrenic LIF expressions between two groups were then statistically analysed. Results: Phrenic nerve activity was more sensitive in response to hypoxia in CIH rats than that in control, showing rapid increases in frequency and amplitude during hypoxic period. The integrated amplitudes at 30 min and 60 min after episodic hypoxia were ( 116.3 ±6.5 ) % and ( 106.1 ± 19.2) %, respectively, from baseline in CIH animals, which were significantly different from those (60.4 ± 7.8 ) % and (48.2 ± 11.0) % in control ( P < 0.01 ), indicating a much larger LTF induced by CIH, the enhanced phrenic LTF. Conclusion: We establish an enhanced phrenic LTF model induced by chronic intermittent hypobaric hypoxia in intact rats, which will provide a useful platform for understanding the mechanism of LTF

  9. Attenuation by phentolamine of hypoxia and levcromakalim-induced abbreviation of the cardiac action potential.

    OpenAIRE

    Tweedie, D.; Boachie-Anash, G.; Henderson, C. G.; Kane, K. A.

    1993-01-01

    1. The effects of phentolamine (5-30 microM) and glibenclamide (10 microM) on action potential characteristics were examined in guinea-pig papillary muscle exposed to either hypoxia or levcromakalim (20 microM). 2. The hypoxia-induced abbreviation of action potential duration (APD) and effective refractory period (ERP) were attenuated but not abolished by glibenclamide (10 microM). Hypoxia reduced APD by 24 +/- 2 vs 65 +/- 4% in glibenclamide- and vehicle-treated tissue, respectively. 3. Phen...

  10. Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

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    Tillmanns Harald H

    2007-02-01

    Full Text Available Abstract Background Chronic hypoxia induces pulmonary arterial hypertension (PAH. Smooth muscle cell (SMC proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA, a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. Methods Mice were held either at normoxia (N; 21% O2 or at hypobaric hypoxia (H; 0.5 atm; ~10% O2. RAPA-treated animals (3 mg/kg*d, i.p. were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel. The ratio of right ventricle to left ventricle plus septum (RV/[LV+S] was used to determine right ventricular hypertrophy. Results Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38 compared to N (median: 0.28, p = 0.028 which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003. H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N to 139 (H, p Conclusion Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.

  11. [The effect of vaporization with thermal sulfurous water on phospholipids in the broncho-alveolar lavage solution following hypobaric hypoxia in the rat].

    Science.gov (United States)

    Prévost, M C; Montastruc, P; Douste-Blazy, L

    1983-09-01

    We have studied, in the rat, the action of a vaporization with sulphurous water from Bagnères de Luchon on the surfactant modifications caused by hypoxia. The phospholipase activity, subordinate to hypoxia, decreased by 1/5 compared to its value without treatment and the phospholipid composition of the broncho-alveolar lung lavage remained unchanged whereas after hypoxia without treatment the phosphatidylcholines level decreases by 26%. We demonstrated by a dose-response study that this protective action decreased with the thermal water dilution. We also showed that this effect could not be due to the only action of reduced sulphur: different concentrations of sulphur solutions had no action on the phospholipase A activity subordinate to hypoxia. So we can conclude that a vaporization with sulphurous water had a protective action against hypoxia on the broncho-alveolar lavage of rat lung.

  12. Disodium cromoglycate attenuates hypoxia induced enlargement of end-expiratory lung volume in rats.

    Science.gov (United States)

    Maxová, H; Hezinová, A; Vízek, M

    2011-01-01

    Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06).

  13. Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.

    Science.gov (United States)

    Bart, Nicole K; Curtis, M Kate; Cheng, Hung-Yuan; Hungerford, Sara L; McLaren, Ross; Petousi, Nayia; Dorrington, Keith L; Robbins, Peter A

    2016-08-01

    Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days (days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 (P iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.

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

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    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.

  15. Correlation offatty liver with hypobaric hypoxia in plateau encamping soldiers for short time%高原驻训官兵肝脏脂肪变性与缺氧等关系探讨

    Institute of Scientific and Technical Information of China (English)

    丰惠; 贾宁阳; 刘燕; 李长英; 沈海明; 李治群; 王洪武

    2016-01-01

    目的:探讨高原缺氧环境对驻训官兵肝脏代谢的影响。方法选择某部2013年4-8月进入西藏高原驻训士兵共计39例,分别于驻训前后进行肝脏CT扫描、血脂三项及血氧饱和度测定。结果驻训后受检者肝CT值、血氧饱和度降低,总胆固醇、甘油三脂均有不同程度升高,与驻训前相比差异均有统计学意义( P<0.05);低密度脂蛋白驻训前后差异不存在统计学意义(P>0.05);驻训后男女间肝CT值、驻训前后总胆固醇及低密度脂蛋白差异存在统计学意义(P<0.05),而在驻训前男女间肝CT值、驻训前后甘油三脂、血氧饱和度差异不存在统计学意义(P>0.05)。驻训前肝CT值与血脂三项呈负相关(分别为:r=-0.812、-0.731、-0.769,均P<0.01)。驻训后CT值与血脂三项呈负相关(分别为:r=-0.791、-0.759、-0.700,均P<0.01),与血氧饱和度呈正相关( r=0.516,P<0.01)。结论高原缺氧环境对驻训官兵肝脏代谢有影响,可引起肝脏脂肪变性及血脂升高,男性影响大于女性。%Objective To investigate the effect of hypobaric hypoxia on liver in encamping soldiers. Methods 39 encamping soldiers were chosen from April to August 2013 to participate in the plateau as research subjects, monitoring the changes of CT scan, blood fat, blood oxygen saturation before and after encamping. Results Both the level of CT value and blood oxygen saturation was de⁃creased;there was significant difference before and after encamping. Both the level of total cholesterol and triglyceride was increased;there was significant difference before and after encamping. There was no significant difference in low density lipoprotein before and af⁃ter encamping ( P>0.05) . There was significant difference among different genders in CT value after encamping, total cholesterol and low density lipoprotein before and

  16. Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Hong [Department of Ophthalmology, Qilu Hospital, Shandong University, 107, Wenhua Xi Road, Jinan 250012 (China); The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, 107, Wenhua Xi Road, Jinan 250012 (China); Wu, Xinyi, E-mail: xywu8868@163.com [Department of Ophthalmology, Qilu Hospital, Shandong University, 107, Wenhua Xi Road, Jinan 250012 (China)

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer Hypoxia attenuates Acanthamoeba-induced the production of IL-8 and IFN-{beta}. Black-Right-Pointing-Pointer Hypoxia inhibits TLR4 expression in a time-dependent manner in HCECs. Black-Right-Pointing-Pointer Hypoxia inhibits Acanthamoeba-induced the activation of NF-{kappa}B and ERK1/2 in HCECs. Black-Right-Pointing-Pointer Hypoxia decreases Acanthamoeba-induced inflammatory response via TLR4 signaling. Black-Right-Pointing-Pointer LPS-induced the secretion of IL-6 and IL-8 is abated by hypoxia via TLR4 signaling. -- Abstract: Acanthamoeba keratitis (AK) is a vision-threatening corneal infection that is intimately associated with contact lens use which leads to hypoxic conditions on the corneal surface. However, the effect of hypoxia on the Acanthamoeba-induced host inflammatory response of corneal epithelial cells has not been studied. In the present study, we investigated the effect of hypoxia on the Acanthamoeba-induced production of inflammatory mediators interleukin-8 (IL-8) and interferon-{beta} (IFN-{beta}) in human corneal epithelial cells and then evaluated its effects on the Toll-like receptor 4 (TLR4) signaling, including TLR4 and myeloid differentiation primary response gene (88) (MyD88) expression as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and extracellular signal-regulated kinases 1/2 (ERK1/2). We then studied the effect of hypoxia on a TLR4-specific inflammatory response triggered by the TLR4 ligand lipopolysaccharide (LPS). Our data showed that hypoxia significantly decreased the production of IL-8 and IFN-{beta}. Furthermore, hypoxia attenuated Acanthamoeba-triggered TLR4 expression as well as the activation of NF-{kappa}B and ERK1/2, indicating that hypoxia abated Acanthamoeba-induced inflammatory responses by affecting TLR4 signaling. Hypoxia also inhibited LPS-induced IL-6 and IL-8 secretion, myeloid differentiation primary response gene (88

  17. Protective effect of intermittent hypobaric hypoxia on cardiomyocytes injury induced by hydrogen peroxide%间歇性低压低氧对过氧化氢心肌细胞损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    郭会彩; 熊晨; 李军霞; 张荣; 赵丽娟; 王永利

    2012-01-01

    Objective: To observe the protective effect and mechnism of intermittent hypobaric hypoxia(IHH) on cardiomyocytes induced by hydrogen dioxide. Methods: Male guinea pigs were divided randomly into two groups (n = 10): intermittent hypoxia gtoup(IHH), and control group( non-IHH). The IHH guinea pigs were exposed to a simulated 5 000 m high altitude and hypoxia in hypobaric chamber for 28 d, 6 h/d. The control guinea pigs were kept in tbe same environment as IHH except hypoxia exposure. Cardiornyocytes were enzymabcally isolated from left ventricle of non-CIHH or CIHH guinea pigs. The contractile was assessed in guinea pigs by a video-based motion edge-detection system. The contents and activities of malondialdehydeC MDA), lactatdehydrogenase(IDH) and anboxidant enzymes were evaluated by using biochemical methods. Results: ①Hydrogen peroxide could induce contractile and diastol dysfunction, the latent period was longer in IHH car-diacmyocytes. ②After hydrogen peroxide(300 μmol/L, 10 min) perfusion, LDH and MDA contents in supernatant increased significantly in non-IHH and CIHH cardiomyocytes (P<0.01), Whereas the contents of MDA and LDH in IHH cardiornyocytes were lower than those in non-IHH cardiomyocytes ( P < 0.01). ③ The activities of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of IHH guinea pigs, after hydrogen peroxide (300 μmol/L, 10 min) perfusion, SOD and CAT activities decreased significantly in non-MH and CIHH cardiomyocytes (p<0.01), whereas the activities of SOD and CAT in CIHH cardiomyocytes were still higher than those in non-IHH cardiomyocytes. Conclusion: Dffl had a protective effect on cardiomyocytes injury induced by hydrogen peroxide, which might relate with its antioxidation effects.%目的:观察慢性间歇性低压低氧对过氧化氢所致心肌细胞损伤的保护作用及其机制.方法:雄性豚鼠20只,随机分为两组(n=10):对照组(non-IHH)、低氧组(IHH).低氧

  18. MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.

    Science.gov (United States)

    Qu, Yi; Shi, Jing; Tang, Ying; Zhao, Fengyan; Li, Shiping; Meng, Junjie; Tang, Jun; Lin, Xuemei; Peng, Xiaodong; Mu, Dezhi

    2016-05-01

    Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.

  19. Effect of acute hypobaric hypoxia at high altitude environment on blood pressure of soldiers%低压缺氧环境对急进高原驻训官兵血压的影响

    Institute of Scientific and Technical Information of China (English)

    粱海君; 王熠; 崔海涛

    2011-01-01

    目的 探讨低压缺氧环境对急进高原驻训官兵血压的影响并分析相关因素,为制定有效的防治对策提供科学依据.方法 选择2010年8月至2010年10月某部参加高原驻训的官兵256例为调查对象,按年龄分为<40岁组(192例)和≥40岁组(64例).监测血压,分析血压升高与年龄、吸烟、睡眠障碍以及负性情绪的关系.结果 256例被调查者高血压患病率达32.03%,明显高于成人血压普查的患病率(11.88%);血压升高发生率在≥40岁组(60.94%)、吸烟组(42.00%)、有睡眠障碍组(51 65%)以及有负性情绪组(51.92%)显著高于<40岁组(22.40%)、不吸烟组(17.92%)、无睡眠障碍组(21.21%)以及无负性情绪组(26.96%),差异有统计学意义(P<0.01).结论 低压缺氧环境可增加急进高原驻训官兵高血压的患病率,年龄≥40岁,有吸烟、睡眠障碍及负性情绪更明显,是防治的重点.%Objective To investigate the effect of hypobaric hypoxia of high altitude environment on blood pressure and the factor analysis of acute encamping soldiers,to design appropriate and effective countermeasures to ensure the physical and health of our encamping soldiers. Methods Choose all encamping 256 soldiers from August 2010 to October 2010 to participate in the plateau as research subjects, monitoring of blood pressure changes with age, smoking, sleep disorders and negative emotions. Results All officers and men to participate in the plateau encamping hypertension prevalence rate was 32.03%,significantly higher than the prevalence of adult blood pressure screening 11.88% ;prevalence of elevated blood pressure in,≥40 age group (60.94%),smoking group(42.00%) ,a sleep disorder group(51.65%)and negative mood group(51.92%)was significantly higher than that in the <40 age group (22.40%) .smoking group( 17.92%) ,a sleep disorder group(21.21%)and negative mood group{26.96%) ,P<0.01. Conclusions Hypoxia can increase the prevalence rate

  20. Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression.

    Science.gov (United States)

    Yu, Jianhua; Zhang, Weiguang; Zhang, Rongguo; Jiang, Guixing; Tang, Haijun; Ruan, Xinxian; Ren, Peitu; Lu, Baochun

    2015-11-01

    Hypoxia/reoxygenation (H/R) injury of cholangiocytes causes serious biliary complications during hepatobiliary surgeries. Molecular hydrogen (H2) has been shown to be effective in protecting various cells and organs against oxidative stress injury. Human liver cholangiocytes were used to determine the potential protective effects of hydrogen against cholangiocyte H/R injury and explore the underlying mechanisms. We found that H2 ameliorated H/R-induced cholangiocytes apoptosis. Our study revealed that H2 activated NF-E2-related factor 2 (Nrf2) and downstream cytoprotective protein expression. However, the protective function of H2 was abolished when Nrf2 was silenced. Apoptosis in cholangiocytes isolated from a rat model of liver ischemia/reperfusion injury indicated that H2 significantly attenuates ischemia/reperfusion cholangiocyte injury in vivo. In conclusion, our study shows that H2 protects intrahepatic cholangiocytes from hypoxia/reoxygenation-induced apoptosis in vitro or in vivo, and this phenomenon may depend on activating Nrf2 expression.

  1. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    Science.gov (United States)

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  2. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury.

    Science.gov (United States)

    Kobayashi, Hanako; Gilbert, Victoria; Liu, Qingdu; Kapitsinou, Pinelopi P; Unger, Travis L; Rha, Jennifer; Rivella, Stefano; Schlöndorff, Detlef; Haase, Volker H

    2012-05-15

    Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, whereas activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with downregulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in noninjured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury.

  3. Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

    Directory of Open Access Journals (Sweden)

    Fuady JH

    2014-03-01

    Full Text Available Jerry H Fuady,1,* Mattia R Bordoli,1,* Irene Abreu-Rodríguez,1,* Glen Kristiansen,2 David Hoogewijs,1,** Daniel P Stiehl,1,** Roland H Wenger1,**1Institute of Physiology and Zurich Center for Human Physiology, University of Zurich, Zurich, Switzerland; 2University Hospital Bonn, Institute of Pathology, Bonn, Germany*,**These authors contributed equally to this workAbstract: Hypoxia and the hypoxia-inducible factor (HIF signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2, which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.Keywords: invasion, metastasis, motility, oxygen, tumor, transcriptional

  4. 慢性间歇性低压低氧抑制线粒体途径介导的代谢综合征大鼠心肌组织细胞凋亡%Chronic intermittent hypobaric hypoxia ameliorates myocardial apoptosis through inhibiting mitochondrial pathway in rats with metabolism syndrome

    Institute of Scientific and Technical Information of China (English)

    袁芳; 李艳青; 滕旭; 周京京; 郭赞; 王昕; 张自伟; 张翼

    2015-01-01

    Aim To confirm the inhibitory effect of chronic intermittent hypobaric hypoxia ( CIHH) on my-ocardial apoptosis induced by metabolism syndrome ( MS) , and to investigate its mechanism. Methods A rat model of MS induced by fructose was used. The blood pressure and the plasma content of glucose, tri-glyceride, cholesterol, and insulin after 12 h fasting were detected. HE stain were used to detect the cardi-ac structure. The TUNEL staining and activity of caspase-3 were used to detect the apoptosis of myocar-dium. The protein expression of Bcl-2 and Bax was detected by Western blot . Results Compared with the control rats, the blood pressure and the plasma content of glucose, triglyceride, cholesterol, and insu-lin were all increased in rats with MS. In rats with MS, the impairment of cardiac structure and the increase of apoptosis were also observed. The protein expression of Bcl-2 was significantly down-regulated, and that of Bax was significantly up-regulated in MS rats. The ratio of Bcl-2/Bax was also significantly decreased. Interest-ingly, CIHH could ameliorate all of the above issues. There was no significant difference between control group and CIHH group. Conclusion CIHH may im-prove the increased apoptosis in rats with MS via inhib-iting the mitochondrial pathway of apoptosis. This stud-y might provide new targets for therapy and the preven-tion of MS patients.%目的:证实CIHH( chronic intermittent hypobaric hypoxi-a, CIHH)具有改善代谢综合征( metabolism syndrome, MS)大鼠心肌细胞凋亡的作用,并探讨其机制。方法10%果糖水喂养SD大鼠(250~300) g 42 d制备MS模型,检测动脉血压以及空腹血糖、胆固醇、甘油三酯和胰岛素含量,HE染色观察心肌结构,TUNEL染色和caspase-3活性测定检测心肌细胞凋亡, Western blot 检测 Bcl-2和 Bax 的蛋白表达水平。结果与正常大鼠比较,果糖喂养大鼠表现出明显的高血压、高血糖、高甘油三脂血症、高胆固醇血症和高胰

  5. Ranolazine attenuates the enhanced reverse Na⁺-Ca²⁺ exchange current via inhibiting hypoxia-increased late sodium current in ventricular myocytes.

    Science.gov (United States)

    Wang, Xiao-Jing; Wang, Lei-Lei; Fu, Chen; Zhang, Pei-Hua; Wu, Ying; Ma, Ji-Hua

    2014-01-01

    Ranolazine (RAN), a novel antianginal agent, inhibits the increased late sodium current (INa.L) under many pathological conditions. In this study, the whole-cell patch-clamp technique was used to explore the effects of RAN on INa.L and reverse Na(+)/Ca(2+) exchange current (INCX) in rabbit ventricular myocytes during hypoxia.Tetrodotoxin (TTX) at 2 μM or RAN at 9 μM decreased significantly INa.L and reverse INCX under normoxia and RAN had no further effects on both currents in the presence of TTX. RAN (3, 6, and 9 μM) attenuated hypoxia-increased INa.L and reverse INCX in a concentration-dependent manner. Hypoxia-increased INa.L and reverse INCX were inhibited by 2 μM TTX, whereas 9 μM RAN applied sequentially did not further decrease both currents. In another group, after both currents were decreased by 9 μM RAN, 2 μM TTX had no further effects in the presence of Ran. In monophasic action potential (MAP) recording, early after-depolarizations (EADs) were suppressed by RAN (9 μM) during hypoxia. In conclusion, RAN decreased reverse INCX by inhibiting INa.L in normoxia, concentration-dependently attenuated the increase of INa.L, which thereby decreased the reverse INCX, and obviously relieved EADs during hypoxia.

  6. Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice.

    Science.gov (United States)

    Jin, Yuling; Wang, Wang; Chai, Sanbao; Liu, Jie; Yang, Ting; Wang, Jun

    2015-12-01

    Hypoxic pulmonary hypertension (HPH), which is characterized by pulmonary arteriolar remodeling and right ventricular hypertrophy, is still a life-threatening disease with the current treatment strategies. The underlying molecular mechanisms of HPH remain unclear. Our previously published study showed that Wnt5a, one of the ligands in the Wnt family, was critically involved in the inhibition of hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin/cyclin D1 in vitro. In this study, we investigated the possible functions and mechanisms of Wnt5a in HPH in vivo. Recombinant mouse Wnt5a (rmWnt5a) or phosphate buffered saline (PBS) was administered to male C57/BL6 mice weekly from the first day to the end of the two or four weeks after exposed to hypoxia (10% O2). Hypoxia-induced pulmonary hypertension was associated with a marked increase in β-catenin/cyclin D1 expression in lungs. Right ventricular systolic pressure and right ventricular hypertrophy index were reduced in animals treated with rmWnt5a compared with PBS. Histology showed less pulmonary vascular remodeling and right ventricular hypertrophy in the group treated with rmWnt5a than with PBS. Treatment with rmWnt5a resulted in a concomitant reduction in β-catenin/cyclin D1 levels in lungs. These data demonstrate that Wnt5a exerts its beneficial effects on HPH by regulating pulmonary vascular remodeling and right ventricular hypertrophy in a manner that is associated with reduction in β-catenin/cyclin D1 signaling. A therapy targeting the β-catenin/cyclin D1 signaling pathway might be a potential strategy for HPH treatment.

  7. [Hypobaric chamber as a test of the aircrew of Russain Air Forces].

    Science.gov (United States)

    Shishov, A A; Olenev, N I; Shishkin, A N; Filatov, V N

    2014-04-01

    Authors research clinical medical importance of hypobaric ascends to an attitude of 5000 meters for 20 minutes for detection of latent forms of diseases and assessment of professional health and ascends to an attitude of 5000 and 6000 meters for 5 minutes when performing psychophysiological training for high altitude flying. According to test of 1326 pilots of Russian Air Forces, including pilots with different diseases, hypobaric ascends showed high diagnostic effectiveness for the professional health assessment. By using of both methods it was revealed that frequency of detection of decreased tolerance to hypoxia is the same (in average in 2,7 and 3,1% of total number of patients). By ascends in 38 patients (2,9%) was revealed decreased tolerance to hypoxia of medium level. It indicated about low functional state and space capacity of pilots. It was proved that hypobaric ascends of 5000 and 6000 meters for 5 minutes could be considered as an effective method of checkup of aircrew for the aviation physical examination.

  8. Pre-Conditioning with CDP-Choline Attenuates Oxidative Stress-Induced Cardiac Myocyte Death in a Hypoxia/Reperfusion Model

    Science.gov (United States)

    González-Pacheco, Héctor; Méndez-Domínguez, Aurelio; Hernández, Salomón; López-Marure, Rebeca; Vazquez-Mellado, Maria J.; Aguilar, Cecilia; Rocha-Zavaleta, Leticia

    2014-01-01

    Background. CDP-choline is a key intermediate in the biosynthesis of phosphatidylcholine, which is an essential component of cellular membranes, and a cell signalling mediator. CDP-choline has been used for the treatment of cerebral ischaemia, showing beneficial effects. However, its potential benefit for the treatment of myocardial ischaemia has not been explored yet. Aim. In the present work, we aimed to evaluate the potential use of CDP-choline as a cardioprotector in an in vitro model of ischaemia/reperfusion injury. Methods. Neonatal rat cardiac myocytes were isolated and subjected to hypoxia/reperfusion using the coverslip hypoxia model. To evaluate the effect of CDP-choline on oxidative stress-induced reperfusion injury, the cells were incubated with H2O2 during reperfusion. The effect of CDP-choline pre- and postconditioning was evaluated using the cell viability MTT assay, and the proportion of apoptotic and necrotic cells was analyzed using the Annexin V determination by flow cytometry. Results. Pre- and postconditioning with 50 mg/mL of CDP-choline induced a significant reduction of cells undergoing apoptosis after hypoxia/reperfusion. Preconditioning with CDP-choline attenuated postreperfusion cell death induced by oxidative stress. Conclusion. CDP-choline administration reduces cell apoptosis induced by oxidative stress after hypoxia/reperfusion of cardiac myocytes. Thus, it has a potential as cardioprotector in ischaemia/reperfusion-injured cardiomyocytes. PMID:24578622

  9. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    Energy Technology Data Exchange (ETDEWEB)

    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  10. Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9.

    Science.gov (United States)

    Yan, Shuangquan; Wang, Yiran; Liu, Panpan; Chen, Ali; Chen, Mayun; Yao, Dan; Xu, Xiaomei; Wang, Liangxing; Huang, Xiaoying

    2016-01-01

    Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK) in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP-) 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway.

  11. Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9

    Directory of Open Access Journals (Sweden)

    Shuangquan Yan

    2016-01-01

    Full Text Available Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP- 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway.

  12. Megakaryocytic leukemia 1 (MKL1 regulates hypoxia induced pulmonary hypertension in rats.

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    Zhibin Yuan

    Full Text Available Hypoxia induced pulmonary hypertension (HPH represents a complex pathology that involves active vascular remodeling, loss of vascular tone, enhanced pulmonary inflammation, and increased deposition of extracellular matrix proteins. Megakaryocytic leukemia 1 (MKL1 is a transcriptional regulator known to influence cellular response to stress signals in the vasculature. We report here that in response to chronic hypobaric hypoxia, MKL1 expression was up-regulated in the lungs in rats. Short hairpin RNA (shRNA mediated depletion of MKL1 significantly ameliorated the elevation of pulmonary arterial pressure in vivo with a marked alleviation of vascular remodeling. MKL1 silencing also restored the expression of NO, a key vasoactive molecule necessary for the maintenance of vascular tone. In addition, hypoxia induced pulmonary inflammation was dampened in the absence of MKL1 as evidenced by normalized levels of pro-inflammatory cytokines and chemokines as well as reduced infiltration of pro-inflammatory immune cells in the lungs. Of note, MKL1 knockdown attenuated fibrogenesis in the lungs as indicated by picrosirius red staining. Finally, we demonstrate that MKL1 mediated transcriptional activation of type I collagen genes in smooth muscle cells under hypoxic conditions. In conclusion, we data highlight a previously unidentified role for MKL1 in the pathogenesis of HPH and as such lay down groundwork for future investigation and drug development.

  13. Effectiveness of beneficial plant-microbe interactions under hypobaric and hypoxic conditions in an advanced life support system

    Science.gov (United States)

    MacIntyre, Olathe; Stasiak, Michael; Cottenie, Karl; Trevors, Jack; Dixon, Mike

    An assembled microbial community in the hydroponics solution of an advanced life support system may improve plant performance and productivity in three ways: (1) exclusion of plant pathogens from the initial community, (2) resistance to infection, and (3) plant-growth promotion. However, the plant production area is likely to have a hypobaric (low pressure) and hypoxic (low oxygen) atmosphere to reduce structural mass and atmosphere leakage, and these conditions may alter plant-microbe interactions. Plant performance and productivity of radish (Raphanus sativus L. cv. Cherry Bomb II) grown under hypobaric and hypoxic conditions were investigated at the University of Guelph's Controlled Environment Systems Research Facility. Changes in the microbial communities that routinely colonized the re-circulated nutrient solution, roots, and leaves of radishes in these experiments were quantified in terms of similarity in community composition, abundance of bacteria, and community diversity before and after exposure to hypobaric and hypoxic conditions relative to communities maintained at ambient growth conditions. The microbial succession was affected by extreme hypoxia (2 kPa oxygen partial pressure) while hypobaria as low as 10 kPa total pressure had little effect on microbial ecology. There were no correlations found between the physiological profile of these unintentional microbial communities and radish growth. The effects of hypobaric and hypoxic conditions on specific plant-microbe interactions need to be determined before beneficial gnotobiotic communities can be developed for use in space. The bacterial strains Tal 629 of Bradyrhizobium japonicum and WCS417 of Pseudomonas fluorescens, and the plant pathogen Fusarium oxysporum f. sp. raphani will be used in future experiments. B. japonicum Tal 629 promotes radish growth in hydroponics systems and P. fluorescens WCS417 induces systemic resistance to fusarium wilt (F. oxysporum f. sp. raphani) in radish under ambient

  14. Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine

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    Liu Gui-Lai

    2012-01-01

    Full Text Available Abstract Background Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein and 3-beta-HSD (3-beta-hydroxysteroid dehydrogenase in the testis. It was hypothesized that these abnormalities in the testis by hypoxia are associated with oxidative stress and an increase in chaperones of endoplasmic reticulum stress (ER stress and ER stress could be modulated by a reduction in calcium influx. Therefore, we verify that if an application of CPU86017-RS (simplified as RS, a derivative to berberine could alleviate the ER stress and depressed gene expressions of StAR and 3-beta-HSD, and low plasma testosterone in hypoxic rats, these were compared with those of nifedipine. Methods Adult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o. during the last 14 days with nifedipine (Nif, 10 and three doses of RS (20, 40, 80, and normal rats treated with RS isomer (80. Serum testosterone (T and luteinizing hormone (LH were measured. The testicular expressions of biomarkers including StAR, 3-beta-HSD, immunoglobulin heavy chain binding protein (Bip, double-strand RNA-activated protein kinase-like ER kinase (PERK and pro-apoptotic transcription factor C/EBP homologous protein (CHOP were measured. Results In hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine. Conclusion Downregulated StAR and 3-beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress

  15. Hematologic responses to hypobaric hyperoxia.

    Science.gov (United States)

    Larkin, E. C.; Adams, J. D.; Williams, W. T.; Duncan, D. M.

    1972-01-01

    Study of the effects of hypoxia, activity, and G forces on human hematopoiesis in an attempt to elucidate these phenomena more precisely. Eight subjects were exposed to an atmosphere of 100% O2 at 258 mm Hg for 30 days, and thereafter immediately exposed to transverse G forces, simulating the Gemini flights' reentry profile. All subjects displayed a significant continuous decline in red cell mass during the exposure period, as measured by the carbon monoxide-dilution method. The Cr51 method also indicated a decline in red blood corpuscle mass. The decrease in red cell mass was due to suppression of erythropoiesis and to hemolysis. After exposure to hyperoxia, all subjects exhibited elevated plasma hemoglobin levels, decreased reticulocyte counts, and decreased red cell survivals. CO production rates and urine erythropoietin levels were unchanged. Two hours after termination of exposure to hyperoxia, all subjects exhibited increased reticulocyte counts which were sustained for longer than two weeks. The progressive decrease in red cell mass was promptly arrested on return to ground level atmospheres. Within 116 days after exposure to hyperoxia, the hematologic parameters of all eight subjects had returned to control levels.

  16. β-adrenergic response modulated by κ-opioid receptor stimulation is attenuated in the cardiomyocytes of rats following chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    裴建明; 毕辉; 王跃民; 朱妙章; 周京军; 朱运龙

    2003-01-01

    Objective: To study cross-talk between β-opioid receptor and β-adrenoceptor through determination of the intracellular calcium ([Ca2+]i) and cAMP responses in ventricular myocytes of rats subjected to chronic hypoxia for 4 weeks.Methods: Electrically-induced [Ca2+]i transient was measured in single right ventricular myocytes isolated from hearts of chronically hypoxic rats and the age-matched normoxic rats, by using a spectrofluorometric method.Results: β-adrenoceptor stimulation with isoproterenol increased the electrically-induced [Ca2+]i transient and cAMP in myocytes of normoxic rats.U50,488H, a selective β-opioid receptor agonist, at dose (1 μmol/L) which itself had no effect on the [Ca2+]i transient and cAMP, significantly inhibited the effect of isoproterenol.This inhibition was completely abolished in the presence of nor-BNI, a selective κ-opioid receptor antagonist.In the ventricular myocytes of chronically hypoxic rats, the inhibition of U50,488H on the increased [Ca2+]i transient and cAMP with isoproterenol was blunted.Conclusion: Results indicate that the cross-talk between the κ-opioid receptor and β-adrenoceptor is attenuated in the right ventricular myocytes of chronically hypoxic rat.This may be a self-protective mechanism of the heart following chronic hypoxia, which prevents the further decrease of the cardiac function.

  17. Tissue-Related Hypoxia Attenuates Proinflammatory Effects of Allogeneic PBMCs on Adipose-Derived Stromal Cells In Vitro

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    Polina I. Bobyleva

    2016-01-01

    Full Text Available Human adipose tissue-stromal derived cells (ASCs are considered a perspective tool for regenerative medicine. Depending on the application mode ASC/allogeneic immune cell interaction can occur in the systemic circulation under plenty high concentrations of O2 and in target tissues at lower O2 levels. Here we examined the effects of allogeneic PHA-stimulated peripheral blood mononuclear cells (PBMCs on ASCs under ambient (20% oxygen and “physiological” hypoxia (5% O2. As revealed with microarray analysis ASCs under 20% O2 were more affected by activated PBMCs, which was manifested in differential expression of more than 300 genes, whereas under 5% O2 only 140 genes were changed. Altered gene pattern was only partly overlapped at different O2 conditions. Under O2 ASCs retained their proliferative and differentiative capacities, mesenchymal phenotype, and intracellular organelle’ state. ASCs were proinflammatory activated on transcription level that was confirmed by their ability to suppress activation and proliferation of mitogen-stimulated PBMCs. ASC/PBMCs interaction resulted in anti-inflammatory shift of paracrine mediators in conditioning medium with significant increase of immunosuppressive LIF level. Our data indicated that under both ambient and tissue-related O2 ASCs possessed immunosuppressive potential and maintained functional activity. Under “physiological” hypoxia ASCs were less susceptible to “priming” by allogeneic mitogen-activated PBMCs.

  18. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    Science.gov (United States)

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

  19. Electroacupuncture Pretreatment Attenuates Cerebral Ischemic Injury via Notch Pathway-Mediated Up-Regulation of Hypoxia Inducible Factor-1α in Rats.

    Science.gov (United States)

    Zhao, Yu; Deng, Bin; Li, Yichong; Zhou, Lihua; Yang, Lei; Gou, Xingchun; Wang, Qiang; Chen, Guozhong; Xu, Hao; Xu, Lixian

    2015-11-01

    We have reported electroacupuncture (EA) pretreatment induced the tolerance against focal cerebral ischemia through activation of canonical Notch pathway. However, the underlying mechanisms have not been fully understood. Evidences suggest that up-regulation of hypoxia inducible factor-1α (HIF-1α) contributes to neuroprotection against ischemia which could interact with Notch signaling pathway in this process. Therefore, the current study is to test that up-regulation of HIF-1α associated with Notch pathway contributes to the neuroprotection of EA pretreatment. Sprague-Dawley rats were treated with EA at the acupoint "Baihui (GV 20)" 30 min per day for successive 5 days before MCAO. HIF-1α levels were measured before and after reperfusion. Then, HIF-1α antagonist 2ME2 and γ-secretase inhibitor MW167 were used. Neurologic deficit scores, infarction volumes, neuronal apoptosis, and Bcl2/Bax were evaluated. HIF-1α and Notch1 intracellular domain (NICD) were assessed. The results showed EA pretreatment enhanced the neuronal expression of HIF-1α, reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis, up-regulated expression of Bcl-2, and down-regulated expression of Bax after reperfusion in the penumbra, while the beneficial effects were attenuated by 2ME2. Furthermore, intraventricular injection with MW167 efficiently suppressed both up-regulation of NICD and HIF-1α after reperfusion. However, administration with 2ME2 could only decrease the expression of HIF-1α in the penumbra. In conclusion, EA pretreatment exerts neuroprotection against ischemic injury through Notch pathway-mediated up-regulation of HIF-1α.

  20. 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...

  1. Metabolomic analysis of anti-hypoxia and anti-anxiety effects of Fu Fang Jin Jing Oral Liquid.

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    Xia Liu

    Full Text Available BACKGROUND: Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics. METHODS: In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin and oxygen consumption increasing (exhaustive swimming were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified. RESULTS: Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect. CONCLUSIONS: FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug

  2. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

    Institute of Scientific and Technical Information of China (English)

    Yan Deng; Xue-Ling Guo; Xiao Yuan; Jin Shang; Die Zhu; Hui-Guo Liu

    2015-01-01

    Background:The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known.The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves.Methods:Eight-week-old male C57BL/6 mice were used.For each exposure time point,eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression.Whereas in the 21 days-Brilliant Blue G (BBG,a selective P2X7R antagonist) study,48 mice were randomly divided into CIH group,BBG-treated CIH group,RA group and BBG-treated RA group.The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR).The spatial learning was analyzed by Morris water maze.The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Westem blotting.The expressions of tumor necrosis factor α,interleukin 1 β (IL-β),IL-18,and IL-6 were measured by real-time PCR.The malondialdehyde and superoxide dismutase levels were detected by colorimetric method.Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method.Results:The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure.In the BBG study,the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test.The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group.BBG alleviated CIH-induced neural injury and consequent functional deficits.Conclusions:The P2X7R antagonism attenuates the CIH-induced neuroinflammation,oxidative stress,and spatial deficits,demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  3. Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

    Science.gov (United States)

    Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats...

  4. Loss of PINK1 attenuates HIF-1α induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia.

    Science.gov (United States)

    Lin, William; Wadlington, Natasha L; Chen, Linan; Zhuang, Xiaoxi; Brorson, James R; Kang, Un Jung

    2014-02-19

    Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.

  5. Prognozing of the Resistance to Hypoxia in Military Pilots by Cardiovascular and Respiratory Parameters

    Science.gov (United States)

    2001-06-01

    Roumen Zlatev, Mirtcho Vukov Rouja Nikolova, M.D. Ph.D. National Center of Hygiene, Medical Ecology and Nutrition Department of Occupational Medicine...results were reported on exposure to acute hypobaric hypoxia at 6000 m (24). Reduced cardiac sensitivity to adrenergic stimulation investigated by...Katch (Eds.) Exercise Physiology. Energy, Nutrition and Human Performance, Williams & Wilkins, Baltimore 1996, 483-527. 42. Meersman R. Respiratory sinys

  6. Folic Acid Attenuates Vascular Endothelial Cell Injury Caused by Hypoxia via the Inhibition of ERK1/2/NOX4/ROS Pathway.

    Science.gov (United States)

    Cheng, Fei; Lan, Jun; Xia, Wenhao; Tu, Chang; Chen, Benfa; Li, Shicheng; Pan, Weibiao

    2016-06-01

    Coronary artery disease is a disease with high morbidity and mortality, in which vascular endothelial dysfunction plays an important role. Hypoxia leads to the inflammation and oxidative stress in endothelial cells, which results in the endothelial injury. The present study was designed to investigate the protective effect and mechanism of folic acid on hypoxia-induced injury in human umbilical vein endothelial cells (HUVEC). Cell counting Kit was used to detect cell survival rate, and apoptotic cells were detected by Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured using dichloro-dihydro-fluorescein diacetate staining. Western blot was used to determine the protein expressions of extracellular signal protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2), NOX4 subunit of NAPDH and endothelial nitric oxide synthase (eNOS). Folic acid significantly increased the cell survival rate and decreased the apoptosis of HUVECs treated with folic acid compared with hypoxia-treated HUVEC. Folic acid also decreased ROS level, while it increased the nitrite content in HUVECs. In addition, folic acid decreased protein expressions of NOX4 and p-ERK1/2, while it increased the protein expression of eNOS in HUVECs. Furthermore, N-acetyl cysteine (NAC), the antioxidant, had similar effect on the cell survival rate and the apoptosis. In addition, DPI (NOX4 inhibitor) and U0126 (ERK1/2 inhibitor) rather than NAC decreased the protein expression of NOX4. NAC, DPI, and U0126 increased the protein expression of eNOS. Furthermore, U0126 rather than DPI and NAC decreased the protein expression of p-ERK1/2. Taken together, the results suggested that hypoxia decreased the cell survival rate and induced apoptosis via ERK1/2/NOX4/ROS pathway, which could be the target of folic acid in protecting the HUVECs from injury caused by hypoxia.

  7. Performances in extreme environments: effects of hyper/hypobarism and hypogravity on skeletal muscle

    Directory of Open Access Journals (Sweden)

    Gerardo Bosco

    2010-09-01

    Full Text Available Many environmental factors may affect muscle plasticity but some have exclusive characteristics that allow them to play a key role to maintain the muscle capacity to generate force; these factors are: i the oxygen availability and ii the load applied to muscle fibres. Hyperbarism is a condition that occurs when a man is subjected to pressure increases. To keep the lungs from collapsing, the air is supplied to him under high pressure which exposes the blood in the lungs to high alveolar gas pressures. Under this condition, the PO2 become sufficiently increased, serious disorders may occur, such as modification of oxygen delivery and/or oxygen availability to permit regular muscle contraction. Also altitude hypobaric hypoxia induces modification of muscle capacity to generate work. Prolonged exposure to high altitude leads significant loss in body mass, thigh muscle mass, muscle fiber area and volume density of muscle mitochondria. Spaceflight results in a number of adaptations to skeletal muscle, including atrophy and early muscle fatigue. Muscle atrophy is observed in a wide range of muscles, with the most extensive loss occurring in the legs, because astronauts are no longer needed to support the body's weight. This review will describe the background on these topics suggesting the strategies to correct the specific muscle changes in presence of environmental stresses, such as the alteration in oxygen-derived signaling pathways or the metabolic consequence of microgravity that may indicate rational interventions to maintain muscle mass and function.

  8. The quality of sweet cherries stored under hypobaric conditions

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    H. Borecka

    2013-12-01

    Full Text Available Sweet cherries cvs 'Emperor Francis' and 'Grosse Schwarze Knorpelkirsche' were stored under hypobaric conditions, 5 kPa and 25 kPa at 2°C. These sweet cherries could be stored for 30 days without a high losses. Sweet cherries of both cvs tasted the best after storage under LPS, worse under CA, and the worst in normal air. Titrate acidity decreased during the storage period, the percent of soluble solids decreased for 15 days after which it increased. Mostly Botrytis cinerea and Monilinia spp. destroyed the sweet cherries during storage. Penicillium spp. affected fruits by less than 1% under kPa, and those subsequently stored for 3 days at 20°C. Hypobaric storage 5 kPa at 2°C seems to be patricularly good for storage of sweet cherries cv. 'Emperor Francis'.

  9. The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference

    Energy Technology Data Exchange (ETDEWEB)

    Doi, Nobutaka [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); New Products Research & Development, Gene Engineering Division, NIPPON GENE Co., Ltd. (Japan); Ogawa, Ryohei, E-mail: ogawa@med.u-toyama.ac.jp [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); Cui, Zheng-Guo [Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama (Japan); Morii, Akihiro; Watanabe, Akihiko [Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama (Japan); Kanayama, Shinji; Yoneda, Yuko [New Products Research & Development, Gene Engineering Division, NIPPON GENE Co., Ltd. (Japan); Kondo, Takashi [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan)

    2015-05-01

    The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1α and HIF-2α seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1α and HIF-2α. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. - Highlights: • Incubation with CoCl{sub 2} confers radioresistance to HeLa cells. • Both HIF-1α and HIF-2α are involved in the acquisition of radioresistance. • An shRNA to a homology region of HIF-1α and HIF-2α suppressed the radioresistance. • The shRNA decreased cells with stem cell markers and a stem cell phenotype.

  10. The Effects of Portulaca oleracea on Hypoxia-Induced Pulmonary Edema in Mice

    Science.gov (United States)

    Yue, Tan; Xiaosa, Wen; Ruirui, Qi; Wencai, Shi; Hailiang, Xin

    2015-01-01

    Abstract Tan Yue, Wen Xiaosa, Qi Ruirui, Shi Wencai, Xin Hailiang, and Li Min. The effects of Portulaca oleracea on hypoxia-induced pulmonary edema in mice. High Alt Med Biol 16:43–51, 2015—Portulaca oleracea L. (PO) is known as “a vegetable for long life” due to its antioxidant, anti-inflammatory, and other pharmacological activities. However, the protective activity of the ethanol extract of PO (EEPO) against hypoxia-induced pulmonary edema has not been fully investigated. In this study, we exposed mice to a simulated altitude of 7000 meters for 0, 3, 6, 9, and 12 h to observe changes in the water content and transvascular leakage of the mouse lung. It was found that transvascular leakage increased to the maximum in the mouse lung after 6 h exposure to hypobaric hypoxia. Prophylactic administration of EEPO before hypoxic exposure markedly reduced the transvascular leakage and oxidative stress, and inhibited the upregulation of NF-kB in the mouse lung, as compared with the control group. In addition, EEPO significantly reduced the levels of proinflammatory cytokines and cell adhesion molecules in the lungs of mice, as compared with the hypoxia group. Our results show that EEPO can reduce initial transvascular leakage and pulmonary edema under hypobaric hypoxia conditions. PMID:25761168

  11. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Yan Deng

    2015-01-01

    Conclusions: The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  12. The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines.

    Science.gov (United States)

    Sinnberg, Tobias; Noor, Seema; Venturelli, Sascha; Berger, Alexander; Schuler, Paul; Garbe, Claus; Busch, Christian

    2014-03-01

    Intravenous application of high-dose ascorbate is used in complementary palliative medicine to treat cancer patients. Pharmacological doses of ascorbate in the mM range induce cytotoxicity in cancer cells mediated by reactive oxygen species (ROS), namely hydrogen peroxide and ascorbyl radicals. However, little is known about intrinsic or extrinsic factors modulating this ascorbate-mediated cytotoxicity. Under normoxia and hypoxia, ascorbate IC50 values were determined on the NCI60 cancer cells. The cell cycle, the influence of cobalt chloride-induced hypoxia-inducible factor-1α (HIF-1α) and the glucose transporter 1 (GLUT-1) expression (a pro-survival HIF-1α-downstream-target) were analysed after ascorbate exposure under normoxic and hypoxic conditions. The amount of ascorbyl radicals increased with rising serum concentrations. Hypoxia (0.1% O2 ) globally increased the IC50 of ascorbate in the 60 cancer cell lines from 4.5 ± 3.6 mM to 10.1 ± 5.9 mM (2.2-fold increase, P ascorbate. This ascorbate resistance depended on HIF-1α-signalling, but did not correlate with cell line-specific expression of the ascorbate transporter GLUT-1. However, under normoxic and hypoxic conditions, ascorbate treatment at the individual IC50 reduced the expression of GLUT-1 in the cancer cells. Our data show a ROS-induced, HIF-1α- and O2 -dependent cytotoxicity of ascorbate on 60 different cancer cells. This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate.

  13. Interleukin-1beta exacerbates hypoxia-induced neuronal damage, but attenuates toxicity produced by simulated ischaemia and excitotoxicity in rat organotypic hippocampal slice cultures.

    Science.gov (United States)

    Pringle, A K; Niyadurupola, N; Johns, P; Anthony, D C; Iannotti, F

    2001-06-01

    Using organotypic hippocampal slice cultures we have investigated the actions of Interleukin-1 (IL-1) in a number of injury paradigms. Low concentrations of IL-1 potentiated hypoxia-induced neurodegeneration whilst high concentrations had no effect. In contrast, higher concentrations of IL-1 were strongly neuroprotective in models of combined oxygen/glucose deprivation and N-methyl-D-aspartate toxicity, but no potentiation was observed at low IL-1 concentrations. Both protective and toxic effects of IL-1 were fully antagonized by IL-1 receptor antagonist. These data demonstrate that the effects of IL-1 on neuronal injury are complex, and may be directly related to the injury paradigm studied.

  14. Endurance training attenuates the bioenergetics alterations of rat skeletal muscle mitochondria submitted to acute hypoxia:Role of ROS and UCP3%耐力训练抑制急性低氧时骨骼肌线粒体生物能学变化:ROS和UCP3的作用

    Institute of Scientific and Technical Information of China (English)

    薄海; 王义和; 李海英; 赵娟; 张红英; 佟长青

    2008-01-01

    The physiological significance of skeletal muscle mitochondrial uncoupling protein 3(UCP3)in hypoxia is elusive.In the current study,UCP3 mRNA and protein expressions were investigated along with mitochondrial respiratory function,reactive oxygen species(ROS)generation,as well as manganese superoxide dismutase(MnSOD)expression in rat skeletal muscle with or without endurance training after an acute and severe hypobaric hypoxia exposure for different time.Acute hypoxia induced a series of impairments in skeletal muscle mitochondrial bioenergetics.In untrained rats,UCP3 protein content increased by 60%above resting level at 4 h hypoxia,whereas MnSOD protein content and activity were unaltered.UCP3 upregulation increased mitochondrial uncoupling respiration thus reducing 02 generation,but inevitably decreased ATP production.Training decreased acute hypoxia-induced upregulation of UCP3 protein(67% vs 42%)in rat skeletal muscle.ROS production in trained rats also showed a dramatic decrease at 2 h,4 h and 6 h,respectively,compared with that in untrained rats.MnSOD protein contents and activities were significantly(50%and 34%)higher in trained than those in untrained rats.Training adaptation of MnSOD may enhance the mitochondrial tolerante to ROS production,and reduce UCP3 activation during severe hypoxia.thus maintaining the efficiency of oxidative phosphorylation.In trained rats,mitochondrial respiratory control(RCR)and P/O ratios were maintained relatively constant despite severe hypoxia.whereas in untrained rats RCR and P/O ratios were significantly decreased.These results indicate that(1)UCP3 mRNA and protein expression in rat skeletal muscle are upregulated during acute and severe hypobaric hypoxia,which may reduce the increased cross-membrane potential(△Ψ)and thus ROS production;(2)Endurance training can blunt hypoxia-induced UCP3 upregulation,and improve mitochondrial efficiency of oxidative phosphorylation due to increased removal of ROS.%骨

  15. Combined intermittent hypoxia and surface muscle electrostimulation as a method to increase peripheral blood progenitor cell concentration

    Directory of Open Access Journals (Sweden)

    Azqueta Carmen

    2009-10-01

    Full Text Available Abstract Background Our goal was to determine whether short-term intermittent hypoxia exposure, at a level well tolerated by healthy humans and previously shown by our group to increase EPO and erythropoiesis, could mobilize hematopoietic stem cells (HSC and increase their presence in peripheral circulation. Methods Four healthy male subjects were subjected to three different protocols: one with only a hypoxic stimulus (OH, another with a hypoxic stimulus plus muscle electrostimulation (HME and the third with only muscle electrostimulation (OME. Intermittent hypobaric hypoxia exposure consisted of only three sessions of three hours at barometric pressure 540 hPa (equivalent to an altitude of 5000 m for three consecutive days, whereas muscular electrostimulation was performed in two separate periods of 25 min in each session. Blood samples were obtained from an antecubital vein on three consecutive days immediately before the experiment and 24 h, 48 h, 4 days and 7 days after the last day of hypoxic exposure. Results There was a clear increase in the number of circulating CD34+ cells after combined hypobaric hypoxia and muscular electrostimulation. This response was not observed after the isolated application of the same stimuli. Conclusion Our results open a new application field for hypobaric systems as a way to increase efficiency in peripheral HSC collection.

  16. Acetylcholine Attenuates Hypoxia/ Reoxygenation-Induced Mitochondrial and Cytosolic ROS Formation in H9c2 Cells via M2 Acetylcholine Receptor

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    Yi Miao

    2013-02-01

    Full Text Available Background: The anti-infammatory and cardioprotective effect of acetylcholine (ACh has been reported; nevertheless, whether and how ACh exhibits an antioxidant property against ischemia/reperfusion (I/R-induced oxidative stress remains obscure. Methods: In the present study, H9c2 rat cardiomyocytes were exposed to hypoxia/reoxygenation (H/R to mimic I/R injury. We estimated intracellular different sources of reactive oxygen species (ROS by measuring mitochondrial ROS (mtROS, mitochondrial DNA (mtDNA copy number, xanthine oxidase (XO and NADPH oxidase (NOX activity and expression of rac 1. Cell injury was determined by lactate dehydrogenase (LDH release and cleaved caspase-3 expression. The siRNA transfection was performed to knockdown of M2 acetylcholine receptor (M2 AChR expression. Results: 12-h hypoxia followed by 2-h reoxygenation resulted in an abrupt burst of ROS in H9c2 cells. Administration of ACh reduced the levels of ROS in a concentration-dependent manner. Compared to the H/R group, ACh decreased mtROS, recovered mtDNA copy number, diminished XO and NOX activity, rac 1 expression as well as cell injury. Co- treatment with atropine rather than hexamethonium abolished the antioxidant and cardioprotective effect of ACh. Moreover, knockdown of M2 AChR by siRNA showed the similar trends as atropine co-treatment group. Conclusions: ACh inhibits mitochondria-, XO- and NOX-derived ROS production thus protecting H9c2 cells against H/R-induced oxidative stress, and these benefcial effects are mainly mediated by M2 AChR. Our findings suggested that increasing ACh release could be a potential therapeutic strategy for treatment and prevention of I/R injury.

  17. Role of metabolic gases in bubble formation during hypobaric exposures.

    Science.gov (United States)

    Foster, P P; Conkin, J; Powell, M R; Waligora, J M; Chhikara, R S

    1998-03-01

    Our hypothesis is that metabolic gases play a role in the initial explosive growth phase of bubble formation during hypobaric exposures. Models that account for optimal internal tensions of dissolved gases to predict the probability of occurrence of venous gas emboli were statistically fitted to 426 hypobaric exposures from National Aeronautics and Space Administration tests. The presence of venous gas emboli in the pulmonary artery was detected with an ultrasound Doppler detector. The model fit and parameter estimation were done by using the statistical method of maximum likelihood. The analysis results were as follows. 1) For the model without an input of noninert dissolved gas tissue tension, the log likelihood (in absolute value) was 255.01. 2) When an additional parameter was added to the model to account for the dissolved noninert gas tissue tension, the log likelihood was 251.70. The significance of the additional parameter was established based on the likelihood ratio test (P bubble formation was 19. 1 kPa (143 mmHg). 4) The additional gas tissue tension, supposedly due to noninert gases, did not show an exponential decay as a function of time during denitrogenation, but it remained constant. 5) The positive sign for this parameter term in the model is characteristic of an outward radial pressure of gases in the bubble. This analysis suggests that dissolved gases other than N2 in tissues may facilitate the initial explosive bubble-growth phase.

  18. Estrogen Effects after a Crush Muscle Injury and Acute Exposure to Hypobaric Hypoxia

    Science.gov (United States)

    2015-03-01

    DUKES DR. RICHARD A. HERSACK Chief, Aircrew Selection & Performance Res Chair , Aeromedical Research Dept This report is published...physical activity. In the Gorzek et al. study, the mice were given free access to a running wheel , and the OE mice exhibited a significantly higher...Moran AL, Lowe DA. Estradiol and tamoxifen reverse ovariectomy-induced physical inactivity in mice. Med Sci Sports Exerc. 2007; 39(2):248-256. 12

  19. Cerebrovascular Responses to Incremental Exercise During Hypobaric Hypoxia: Effect of Oxygenation on Maximal Performance

    Science.gov (United States)

    2008-01-01

    cerebral (frontal lobe) (COX) and muscle (vastus lateralis) oxygenation ( MOX ) (near infrared spectros- copy), middle cerebral artery blood flow...PETCO2 and COX dropped throughout exercise, while MCA Vmean fell only from 75 to 100% Ẇmax. MOX fell from rest to 75% Ẇmax at SL and AH and...throughout exercise in CH. The magnitude of fall in COX, but not MOX , was different between conditions (CH AH SL). FIO2 0.60 at Ẇmax did not prolong

  20. Effects of Hypobaric Treatments on the Quality, Bioactive Compounds, and Antioxidant Activity of Tomato.

    Science.gov (United States)

    Kou, Xiaohong; Wu, Ji Yun; Wang, Yong; Chen, Qiong; Xue, Zhaohui; Bai, Yang; Zhou, Fengjuan

    2016-07-01

    Hypobaric treatment is becoming a potential technology to protect fruits from postharvest decay. The objective of this study was to investigate the effects of hypobaric treatments on storage quality, bioactive compounds, and antioxidant activity of tomato fruit. In this study, green tomatoes (cv. "Fen guan") were treated with hypobaric pressures (0.04 and 0.07 MPa) at ambient temperature (20 ℃) for 28 d. The results showed that under hypobaric storage, the respiration rates significantly declined and the respiratory peaks postponed 12 and 8 d by 0.04 and 0.07 MPa treatments, respectively, compared to control. Total soluble solid, titratable acidity, ascorbic acid, and lycopene were retained by hypobaric treatment. Moreover, ascorbic acid contents treated with 0.04 and 0.07 MPa were, respectively, 37% and 26% higher than control at day 24 and the contents of total polyphenols were, respectively, 1.28 and 1.11 times higher than control. Production and accumulation of toxic substances were significantly restrained. The ethanol content decreased, respectively, by 53% and 84% than control. At later storage period, the superoxide dismutase activity in treated fruits was about 0.58 U/(g·FW·min), whereas only 0.29 U/(g·FW·min) in control. Hypobaric treatment not only maintained a high activity of superoxide dismutase and peroxidase (POD), but also improved antioxidant capacity. All the results indicated that hypobaric treatment was a potential helpful method to protect the quality and nutrition of tomato and prolong ripening of tomato. Furthermore, the effect of 0.04 MPa hypobaric treatment was found better than 0.07 MPa.

  1. Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Nordsborg, Nikolai; Taudorf, Sarah;

    2012-01-01

    Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether...... these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric...... hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P...

  2. Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model.

    Science.gov (United States)

    Chaillou, Thomas; Koulmann, Nathalie; Simler, Nadine; Meunier, Adélie; Serrurier, Bernard; Chapot, Rachel; Peinnequin, Andre; Beaudry, Michèle; Bigard, Xavier

    2012-03-01

    Hypoxia induces a loss of skeletal muscle mass, but the signaling pathways and molecular mechanisms involved remain poorly understood. We hypothesized that hypoxia could impair skeletal muscle hypertrophy induced by functional overload (Ov). To test this hypothesis, plantaris muscles were overloaded during 5, 12, and 56 days in female rats exposed to hypobaric hypoxia (5,500 m), and then, we examined the responses of specific signaling pathways involved in protein synthesis (Akt/mTOR) and breakdown (atrogenes). Hypoxia minimized the Ov-induced hypertrophy at days 5 and 12 but did not affect the hypertrophic response measured at day 56. Hypoxia early reduced the phosphorylation levels of mTOR and its downstream targets P70(S6K) and rpS6, but it did not affect the phosphorylation levels of Akt and 4E-BP1, in Ov muscles. The role played by specific inhibitors of mTOR, such as AMPK and hypoxia-induced factors (i.e., REDD1 and BNIP-3) was studied. REDD1 protein levels were reduced by overload and were not affected by hypoxia in Ov muscles, whereas AMPK was not activated by hypoxia. Although hypoxia significantly increased BNIP-3 mRNA levels at day 5, protein levels remained unaffected. The mRNA levels of the two atrogenes MURF1 and MAFbx were early increased by hypoxia in Ov muscles. In conclusion, hypoxia induced a transient alteration of muscle growth in this hypertrophic model, at least partly due to a specific impairment of the mTOR/P70(S6K) pathway, independently of Akt, by an undefined mechanism, and increased transcript levels for MURF1 and MAFbx that could contribute to stimulate the proteasomal proteolysis.

  3. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.

    Directory of Open Access Journals (Sweden)

    Bin Bao

    Full Text Available Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT, maintenance of cancer stem cell (CSC functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.

  4. Effect of acute hypoxia on cognition: A systematic review and meta-regression analysis.

    Science.gov (United States)

    McMorris, Terry; Hale, Beverley J; Barwood, Martin; Costello, Joseph; Corbett, Jo

    2017-03-01

    A systematic meta-regression analysis of the effects of acute hypoxia on the performance of central executive and non-executive tasks, and the effects of the moderating variables, arterial partial pressure of oxygen (PaO2) and hypobaric versus normobaric hypoxia, was undertaken. Studies were included if they were performed on healthy humans; within-subject design was used; data were reported giving the PaO2 or that allowed the PaO2 to be estimated (e.g. arterial oxygen saturation and/or altitude); and the duration of being in a hypoxic state prior to cognitive testing was ≤6days. Twenty-two experiments met the criteria for inclusion and demonstrated a moderate, negative mean effect size (g=-0.49, 95% CI -0.64 to -0.34, p<0.001). There were no significant differences between central executive and non-executive, perception/attention and short-term memory, tasks. Low (35-60mmHg) PaO2 was the key predictor of cognitive performance (R(2)=0.45, p<0.001) and this was independent of whether the exposure was in hypobaric hypoxic or normobaric hypoxic conditions.

  5. Effects of Hypobaric Storage on Physiological and Biochemical Changes in Postharvest Dong Jujube Fruit During Cold Storage

    Institute of Scientific and Technical Information of China (English)

    XUE Meng-lin; ZHANG Ping; ZHANG Ji-shu; WANG Li

    2003-01-01

    Effects of hypobaric storage on physiological and biochemical changes in Dong jujube fruit wereinvestigated. Hypobaric storage significantly delayed the decrease in firmness and maintained content of ascor-bic acid, reduced accumulation of ethanol and acetaldehyde in pulp and respiration, inhibited activities of as-corbic acid oxidase and alcohol dehydrogenase and slowed down the rate of ethylene production, but had littleeffect on flesh browning of the fruit.

  6. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

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

    2016-01-01

    Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular...... response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations...... 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...

  7. 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...

  8. Hypoxia and brain development

    NARCIS (Netherlands)

    Nyakas, Csaba; Buwalda, Bauke; Luiten, P.

    1996-01-01

    Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous an

  9. Intermittent hypoxia stimulates formation of binuclear neurons in brain cortex- a role of cell fusion in neuroprotection?

    Science.gov (United States)

    Paltsyn, Alexander A; Manukhina, Eugenia B; Goryacheva, Anna V; Downey, H Fred; Dubrovin, Ivan P; Komissarova, Svetlana V; Kubatiev, Aslan A

    2014-05-01

    Oligodendrocyte fusion with neurons in the brain cortex is a part of normal ontogenesis and is a possible means of neuroregeneration. Following such fusion, the oligodendrocyte nucleus undergoes neuron-specific reprogramming, resulting in the formation of binuclear neurons, which doubles the functional capability of the neuron. In this study, we tested the hypothesis that the formation of binuclear neurons is involved in long-term adaptation of the brain to intermittent hypobaric hypoxia, which is known to be neuroprotective. Rats were adapted to hypoxia in an altitude chamber at a simulated altitude of 4000 m above sea level for 14 days (30 min increasing to 4 h, daily). One micrometer sections of the left motor cortex were analyzed by light microscopy. Phases of the fusion and reprogramming process were recorded, and the number of binuclear neurons was counted for all section areas containing pyramidal neurons of layers III-V. For the control group subjected to sham hypoxia, the density of binuclear neurons was 4.49 ± 0.32 mm(2). In the hypoxia-adapted group, this density increased to 5.71 ± 0.39 mm(2) (P neurons did not differ from the number observed in the control group. We suggest that the increased content of binuclear neurons may serve as a structural basis for the neuroprotective effects of the adaptation to hypoxia.

  10. ROCK2 and MYLK variants under hypobaric hypoxic environment of high altitude associate with high altitude pulmonary edema and adaptation

    Directory of Open Access Journals (Sweden)

    Pandey P

    2015-11-01

    of ROCK2 and MYLK.Conclusion: The data suggest the association of ROCK2 with HAPE and MYLK with HAPE and adaptation in Indian population. The outcome has provided new insights into the physiology of HAPE and adaptation. Keywords: adaptation, hypobaric hypoxia, ROCK2, MYLK, high altitude pulmonary edema, SNP

  11. Expression of Neuronal and Inducible Nitric Oxide Synthase Isoforms and Generation of Protein Nitrotyrosine in Rat Brain Following Hypobaric Hypoxia

    Science.gov (United States)

    2001-06-01

    compilation report: ADPO11059 thru ADP011100 UNCLASSIFIED 38- 1 Expression of Neuronal and Inducible Nitric Oxide Synthase Isoforms and Generation of Protein...cloned, both from chondrocytes (Charles et al., 1993) and hepatocytes (Geller et al., 1993). The neurotoxic effects of NO is mediated by formation of...injection at multiple sites on the back. Four boosts of 1 /6 of the conjugate emulsified in Freund’s incomplete adjuvant were given by subcutaneous injection

  12. CHOICE - Directed Study: Consequences of longterm- Confinement and Hypobaric HypOxia on Immunity in the Antarctic Concordia Environment

    Science.gov (United States)

    Sams, Clarence; Pierson, Duane; Crucian, Brian; Chouker, Alexander; Feurecker, matthias; Salem, Alexander; Stowe, Raymond; Mehta, Satish; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

    2010-01-01

    Concerning ground-based space physiological research, the choice of analog must carefully match the system of interest. For spaceflight-associated immune dysregulation (SAID), Antarctica winter-over has emerged as potentially the best terrestrial analog. The prolonged mission durations, extreme/dangerous environment, station-based lifestyle, isolation from outside world, disrupted circadian rhythms, and other psychological aspects make this analog extremely high fidelity for exploration-class space missions (long duration lunar, Mars). NASA, ESA and RSA are currently investigating SAID, with NASA currently operating the Integrated Immune flight study. It is desirable to have a ground analog for SAID validated, so that potential countermeasures might be validated terrestrially prior to during flight. For this presentation, NASA data collected on the winterover 2009 crewmembers, baseline through early deployment will be presented. Through early deployment (approximately 2-3 weeks at Concordia), phenotypic alterations included increased levels of memory T cells, shifts among the CD8+ T cell compartment to a more mature phenotype, and increases in constitutively activated T cells. CD8+/IFNg+ T cell percentages, and T cell blastogenesis functional responses were depressed early deployment as compared to healthy controls. In four compatible subjects, secreted T cell Th1/Th2 cytokines were measured following culture stimulation, and a Th2 shift was observed as compared to controls. Post-winter over frozen sample return will be required to determine if this shift persisted during the winter over period. Additionally, circadian rhythms remained altered compared to baseline, as determined through 5x daily cortisol measurements. Latent viral reactivation will not be determined until frozen sample return occurs.

  13. The Effects of Hypobaric Hypoxia on Erythropoiesis, Maximal Oxygen Uptake and Energy Cost of Exercise Under Normoxia in Elite Biathletes

    Directory of Open Access Journals (Sweden)

    Milosz Czuba

    2014-12-01

    Full Text Available The aim of the present study was to evaluate the effects of 3 weeks altitude training according to the HiHiLo (live high-base train high-interval train low procedure as described by Chapman et al. (1998, on erythropoiesis, maximal oxygen uptake and energy cost of exercise under normoxia in elite biathletes. Fifteen male elite biathletes randomly divided into an experimental (H group (n = 7; age 27.1 ± 4.6 years; maximal oxygen uptake (VO2max 66.9 ± 3.3 ml·kg–1·min–1; body height (BH 1.81 ± 0.06 m; body mass (BM 73.1 ± 5.4kg, and a control (C group (n = 8; age 23.2 ± 0.9 years; VO2max 68.2 ± 4.1 ml·kg–1·min–1; BH 1.75 ± 0.03 m; BM 63.1 ± 1.5 kg took part in the study. The H group stayed for 3 weeks at an altitude of 2015 m and performed endurance training on skis four times per week at 3000 m. Additionally, the training protocol included three high-intensity interval sessions at an altitude of 1000 m. The C group followed the same training protocol with skirollers in normoxia at an altitude of 600 m. The HiHiLo protocol applied in our study did not change VO2max or maximal workload (WRmax significantly during the incremental treadmill test in group H. However, the energy cost for selected submaximal workloads in group H was significantly (p < 0.01 reduced compared to group C (-5.7%, -4.4%, -6% vs. -3.5%, -2.1%, -2.4%. Also a significant (p < 0.001 increase in serum EPO levels during the first two weeks of HiHiLo training at 2015 m was observed, associated with a significant (p < 0.05 increase in hemoglobin mass, number of erythrocytes, hematocrit value and percent of reticulocytes compared with initial values (by 6.4%, 5%, 4.6% and 16,6%, respectively. In group C, changes in these variables were not observed. These positive changes observed in our study led to a conclusion that the HiHiLo training method could improve endurance in normoxia, since most of the biathlon competitions are performed at submaximal intensities.

  14. Effects of hypobaria and hypoxia on seed germination of six plant species

    Science.gov (United States)

    Tang, Yongkang; Gao, Feng; Guo, Shuangsheng; Li, Fang

    2014-10-01

    Hypobaria (low pressure) is typically associated with hypoxia (low oxygen partial pressure). There are several advantages of growing higher plants under hypobaria in the moon or mars habitat. The objectives of this research were to investigate the seed germination of six plant species under hypobaric and ambient total pressure conditions. Seeds were sown and germinated under three levels of total atmospheric pressure (101, 30 and 10 kPa) and three levels of oxygen partial pressures (21, 6 and 2 kPa) in an 8-day study. Hypoxia (6 or 2 kPa) significantly inhibited all seed germination under three levels of total atmospheric pressure by increasing the electrical conductivity and the optical density, decreasing the seed germination percentage and seed dehydrogenase activity and inhibiting the growth of the shoots and roots. Hypobaria (30 or 10 kPa) markedly improved seed germination and root growth by enhancing the oxygen diffusion rate under hypoxic conditions (6 or 2 kPa). The seeds of three dicot plants (lettuce, Chinese cabbage and cucumber) were more sensitive to hypoxia caused by hypobaria than were those of three monocot plants (maize, wheat and rice); lettuce and cucumber seeds had the highest sensitivity, whereas rice seeds had the lowest sensitivity. This research demonstrates that six experimental seeds can germinate normally under hypobaria (30 kPa), but the oxygen partial pressure should not be less than 6 kPa.

  15. Hypoxia-mediated metastasis.

    Science.gov (United States)

    Chang, Joan; Erler, Janine

    2014-01-01

    Metastasis is responsible for more than 90 % of deaths among cancer patient. It is a highly complex process that involves the interplay between cancer cells, the tumor microenvironment, and even noncancerous host cells. Metastasis can be seen as a step-wise process: acquisition of malignant phenotype, invasion into surrounding tissue, intravasation into blood vessels, survival in circulation, extravasation to distant sites, and colonization of new organs. Before the actual metastatic process, the secondary site is also prepared for the arrival of the cancer cells through formation of "premetastatic niches." Hypoxia (low oxygen tension) is commonly found in solid tumors more than a few millimeters cubed and often is associated with a poor prognosis. Hypoxia increases angiogenesis, cancer cell survival, and metastasis. This chapter described how hypoxia regulates each step of the metastatic process and how blocking hypoxia-driven metastasis through targeting hypoxia-inducible factor 1, or downstream effector molecules such as the lysyl oxidase family may represent highly effective preventive strategies against metastasis in cancer patients.

  16. Expression and role of factor inhibiting hypoxia-inducible factor-1 in pulmonary arteries of rat with hypoxia-induced hypertension

    Institute of Scientific and Technical Information of China (English)

    Daiyan Fu; Aiguo Dai; Ruicheng Hu; Yunrong Chen; Liming Zhu

    2008-01-01

    Hypoxia-inducible factor-11α subunit (HIF-1α) plays a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH) by transactivating it's target genes. As an oxygen-sensitive attenuator, factor inhibiting HIF-1 (FIH)hydroxylates a conserved asparagine residue within the C-terminal transactivation domain of HIF-1α under normoxia and moderate hypoxia. FIH protein is downregulated in response to hypoxia, but its dynamic expression and role during the development of HPH remains unclear. In this study,an HPH rat model was established. The mean pulmonary arterial pressure increased significantly after 7 d of hypoxia.The pulmonary artery remodeling index became evident after 7 d of hypoxia, while the right ventricular hypertrophy index became significant after 14 d of hypoxia. The messenger RNA (mRNA) and protein expression of HIF-1α and vascular endothelial growth factor (VEGF), a well-characterized target gene of HIF-1α, were markedly upregulated after exposure to hypoxia in pulmonary arteries. FIH protein in lung tissues declined after 7 d of hypoxia and continued to decline through the duration of hypoxia. FIH mRNA had few changes after exposure to hypoxia compared with after exposure to normoxia.In hypoxic rats, FIH protein showed significant negative correlation with VEGF mRNA and VEGF protein. FIH protein was negatively correlated with mean pulmonary arterial pressure, pulmonary artery remodeling index and right ventricular hypertrophy index. Taken together, our results suggest that, in the pulmonary arteries of rat exposed to moderate hypoxia, a time-dependent decrease in FIH protein may contribute to the development of rat HPH by enhancing the transactivation of HIF-1α target genes such as VEGF.

  17. Effects of Chinese herbal monomers on oxidative phosphorylation and membrane potential in cerebral mitochondria isolated from hypoxia-exposed rats in vitro

    Institute of Scientific and Technical Information of China (English)

    Weihua Yan; Junze Liu

    2012-01-01

    Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia. Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation. In this study, effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs. Rats were exposed to a low-pressure environment of 405.35 mm Hg (54.04 kPa) for 3 days to establish high-altitude hypoxic models. Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers (sinomenine, silymarin, glycyrrhizic acid, baicalin, quercetin, ginkgolide B, saffron, piperine, ginsenoside Rg1 and oxymatrine) for 5 minutes in vitro. Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method, respectively. Hypoxic exposure significantly decreased the state 3 respiratory rate, respiratory control rate and mitochondrial membrane potential, and significantly increased the state 4 respiratory rate. Treatment with saffron, ginsenoside Rg1 and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro, while ginsenoside Rg1, piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats. The Chinese herbal monomers saffron, ginsenoside Rg1, piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.

  18. 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.

  19. Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

    Directory of Open Access Journals (Sweden)

    J.M. Marshall

    1998-07-01

    Full Text Available This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS. It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction.

  20. Role of hypoxia-induced anorexia and right ventricular hypertrophy on lactate transport and MCT expression in rat muscle.

    Science.gov (United States)

    Py, Guillaume; Eydoux, Nicolas; Lambert, Karen; Chapot, Rachel; Koulmann, Natahlie; Sanchez, Hervé; Bahi, Lahoucine; Peinnequin, André; Mercier, Jacques; Bigard, André-Xavier

    2005-05-01

    To dissect the independent effects of altitude-induced hypoxemia and anorexia on the capacity for cardiac lactate metabolism, we examined the effects of 21 days of chronic hypobaric hypoxia (CHH) and its associated decrease in food intake and right ventricle (RV) hypertrophy on the monocarboxylate transporter 1 and 4 (MCT) expression, the rate of lactate uptake into sarcolemmal vesicles, and the activity of lactate dehydrogenase isoforms in rat muscles. In comparison with control rats (C), 1 mmol/L lactate transport measured on skeletal muscle sarcolemmal vesicles increased by 33% and 58% in hypoxic (CHH, barometric pressure = 495 hPa) and rats pair-fed an equivalent quantity of food to that consumed by hypoxic animals, respectively. The increased lactate transport was higher in PF than in CHH animals ( P < .05). No associated change in the expression of MCT1 protein was observed in skeletal muscles, whereas MCT1 mRNA decreased in CHH rats, in comparison with C animals (42%, P < .05), partly related to caloric restriction (30%, P < .05). MCT4 mRNA and protein increased during acclimatization to hypoxia only in slow-oxidative muscles (68%, 72%, P < .05, respectively). The MCT4 protein content did not change in the plantaris muscle despite a decrease in transcript levels, related to hypoxia and caloric restriction. In both the left and right ventricles, the MCT1 protein content was unaffected by ambient hypoxia or restricted food consumption. These results suggest that MCT1 and MCT4 gene expression in fast-glycolytic muscles is mainly regulated by posttranscriptional mechanisms. Moreover, the results emphasize the role played by caloric restriction on the control of gene expression in response to chronic hypoxia and suggest that hypoxia-induced right ventricle hypertrophy failed to alter MCT proteins.

  1. The Mechanism of Adaptation of Breast Cancer Cells to Hypoxia: Role of AMPK/mTOR Signaling Pathway.

    Science.gov (United States)

    Sorokin, D V; Scherbakov, A M; Yakushina, I A; Semina, S E; Gudkova, M V; Krasil'nikov, M A

    2016-02-01

    We studied the mechanisms of adaptation of human breast cancer cells MCF-7 to hypoxia and analyzed the role of AMPK/mTOR signaling pathway in the maintenance of cell proliferation under hypoxic conditions. It was found that long-term culturing (30 days or more) of MCF-7 cells under hypoxic conditions induced their partial adaptation to hypoxia. Cell adaptation to hypoxia was associated with attenuation of hypoxia-dependent AMPK induction with simultaneous constitutive activation of mTOR and Akt. These findings suggest that these proteins can be promising targets for targeted therapy of tumors developing under hypoxic conditions.

  2. Exploring the boundary between a siphon and barometer in a hypobaric chamber.

    Science.gov (United States)

    Hughes, Stephen; Gurung, Som

    2014-04-22

    Siphons have been used since ancient times, but exactly how they work is still a matter of debate. In order to elucidate the modus operandi of a siphon, a 1.5 m high siphon was set up in a hypobaric chamber to explore siphon behaviour in a low-pressure environment. When the pressure in the chamber was reduced to about 0.18 atmospheres, a curious waterfall-like feature appeared downstream from the apex of the siphon. A hypothesis is presented to explain the waterfall phenomenon. When the pressure was reduced further the siphon broke into two columns--in effect becoming two back-to-back barometers. This experiment demonstrates the role of atmospheric pressure in explaining the hydrostatic characteristics of a siphon and the role of molecular cohesion in explaining the hydrodynamic aspects.

  3. Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning

    Science.gov (United States)

    Stygall, Jan; Wilson, Mark H.; Martin, Daniel; Levett, Denny; Mitchell, Kay; Mythen, Monty; Montgomery, Hugh E.; Grocott, Mike P.; Aref-Adib, Golnar; Edsell, Mark; Plant, Tracie; Imray, Chris; Cooke, Debbie; Harrington, Jane; Khosravi, Maryam; Newman, Stanton P.

    2017-01-01

    Background The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH) remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m). Methods A neuropsychological (NP) test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5±13.7 years; 60% male). These were studied at baseline (sea level), 3,500 m (Namche Bazaar), 5,300 m (Everest Base Camp) and on return to 1,300 m (Kathmandu) (attrition rate 23.7%). A comparable control group (n = 25; age 44.5±14.1 years; 60% male) for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI) was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls. Results Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95) with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56). However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p < .0001), but was otherwise not consistently associated with socio-demographic, mood, or physiological variables. Conclusions After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease. PMID:28346535

  4. Description of the NASA Hypobaric Decompression Sickness Database (1982-1998)

    Science.gov (United States)

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

    2008-01-01

    The availability of high-speed computers, data analysis software, and internet communication are compelling reasons to describe and make available computer databases from many disciplines. Methods: Human research using hypobaric chambers to understand and then prevent decompression sickness (DCS) during space walks has been conducted at the Johnson Space Center (JSC) from 1982 to 1998. The data are archived in the NASA Hypobaric Decompression Sickness Database, within an Access 2003 Relational Database. Results: There are 548 records from 237 individuals that participated in 31 unique tests. Each record includes physical characteristics, the denitrogenation procedure that was tested, and the outcome of the test, such as the report of a DCS symptom and the intensity of venous gas emboli (VGE) detected with an ultrasound Doppler bubble detector as they travel in the venous blood along the pulmonary artery on the way to the lungs. We documented 84 cases of DCS and 226 cases where VGE were detected. The test altitudes were 10.2, 10.1, 6.5, 6.0, and 4.3 pounds per square inch absolute (psia). 346 records are from tests conducted at 4.3 psia, the operating pressure of the current U.S. space suit. 169 records evaluate the Staged 10.2 psia Decompression Protocol used by the Space Shuttle Program. The mean exposure time at altitude was 242.3 minutes (SD = 80.6), with a range from 120 to 360 minutes. Among our test subjects, 96 records of exposures are females. The mean age of all test subjects was 31.8 years (SD = 7.17), with a range from 20 to 54 years. Discussion: These data combined with other published databases and evaluated with metaanalysis techniques would extend our understanding about DCS. A better understanding about the cause and prevention of DCS would benefit astronauts, aviators, and divers.

  5. Rhodiola crenulata and Its Bioactive Components, Salidroside and Tyrosol, Reverse the Hypoxia-Induced Reduction of Plasma-Membrane-Associated Na,K-ATPase Expression via Inhibition of ROS-AMPK-PKCξ Pathway

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    Shih-Yu Lee

    2013-01-01

    Full Text Available Exposure to hypoxia leads to impaired pulmonary sodium transport, which is associated with Na,K-ATPase dysfunction in the alveolar epithelium. The present study is designed to examine the effect and mechanism of Rhodiola crenulata extract (RCE and its bioactive components on hypoxia-mediated Na,K-ATPase endocytosis. A549 cells were exposed to hypoxia in the presence or absence of RCE, salidroside, or tyrosol. The generation of intracellular ROS was measured by using the fluorescent probe DCFH-DA, and the endocytosis was determined by measuring the expression level of Na,K-ATPase in the PM fraction. Rats exposed to a hypobaric hypoxia chamber were used to investigate the efficacy and underlying mechanism of RCE in vivo. Our results showed that RCE and its bioactive compounds significantly prevented the hypoxia-mediated endocytosis of Na,K-ATPase via the inhibition of the ROS-AMPK-PKCζ pathway in A549 cells. Furthermore, RCE also showed a comparable preventive effect on the reduction of Na,K-ATPase endocytosis and inhibition of AMPK-PKCξ pathway in the rodent model. Our study is the first to offer substantial evidence to support the efficacy of Rhodiola products against hypoxia-associated Na,K-ATPase endocytosis and clarify the ethnopharmacological relevance of Rhodiola crenulata as a popular folk medicine for high-altitude illness.

  6. Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

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    Chua, Su-Kiat; Shyu, Kou-Gi; Lin, Yuh-Feng; Lo, Huey-Ming; Wang, Bao-Wei

    2016-01-01

    Background Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia. Methods and Results Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects. Conclusion Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment. PMID:27792771

  7. Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia

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    Meng-Chuan Chen

    2015-07-01

    Full Text Available Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1 plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24 cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.

  8. Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis.

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    Tuleta, I; França, C N; Wenzel, D; Fleischmann, B; Nickenig, G; Werner, N; Skowasch, D

    2015-01-01

    Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week-intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6±6.2% of maximal phenylephrine-induced vasoconstriction vs. 35.2±4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28±0.05% vs. 0.15±0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0±0.5% vs. 5.3±1.9% in control), despite the elevated number of these cells in the bone marrow (2.0±0.4% vs. 1.1±0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis.

  9. [Effects of palmitic acid on activity of uncoupling proteins and proton leak in in vitro cerebral mitochondria from the rats exposed to simulated high altitude hypoxia].

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    Xu, Yu; Liu, Jun-Ze; Xia, Chen

    2008-02-25

    To reveal the roles of uncoupling proteins (UCPs) in disorder of mitochondrial oxidative phosphorylation induced by free fatty acid during hypoxic exposure, the effects of palmitic acid on activity of UCPs, proton leak and mitochondrial membrane potential in hypoxia-exposed rat brain mitochondria were observed in vitro. Adult Sprague-Dawley (SD) rats were set randomly into control, acute hypoxia and chronic hypoxia groups (n=8 in each group). The acute and chronic hypoxic rats were exposed to simulated 5000 m high altitude in a hypobaric chamber 23 h/d for 3 d and 30 d, respectively. The brain mitochondria were isolated by centrifugation. UCP content and activity were detected by [(3)H]-GTP binding method. The proton leak was measured by TPMP(+) electrode and oxygen electrode. The membrane potential of mitochondria was calculated by detecting the fluorescence from Rodamine 123. Hypoxic exposure resulted in an increase in UCP activity and content as well as proton leak, but a decrease in the membrane potential of rat brain mitochondria. Palmitic acid resulted in further increases in UCP activity and content as well as proton leak, and further decrease in membrane potential of brain mitochondria in vitro from hypoxia-exposed rats, but hypoxic exposure decreased the reactivity of cerebral mitochondria to palmitic acid, especially in the acute hypoxia group. There was a negative correlation between mitochondrial proton leak and K(d) value (representing derivative of UCP activity, PB(max) (representing the maximal content of UCPs in mitochondrial inner membrane, P<0.01, r = 0.856). Cerebral mitochondrial membrane potential was negatively correlated with proton leak (P<0.01, r = -0.880). It is suggested that hypoxia-induced proton leak enhancement and membrane potential decrease are correlated with the increased activity of UCPs. Hypoxia can also decrease the sensitivity of cerebral mitochondria to palmitic acid, which may be a self-protective mechanism in high altitude

  10. Hypoxia and fatty liver.

    Science.gov (United States)

    Suzuki, Tomohiro; Shinjo, Satoko; Arai, Takatomo; Kanai, Mai; Goda, Nobuhito

    2014-11-07

    The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

  11. Sodium hydrosulfide prevents hypoxia-induced behavioral impairment in neonatal mice.

    Science.gov (United States)

    Wang, Zhen; Zhan, Jingmin; Wang, Xueer; Gu, Jianhua; Xie, Kai; Zhang, Qingrui; Liu, Dexiang

    2013-11-13

    Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological abnormalities. Endogenous hydrogen sulfide (H2S) may have multiple functions in brain. The aim of this study is to investigate whether sodium hydrosulfide (NaHS), a H2S donor, provides protection against neonatal hypoxia-induced neurobehavioral deficits. Neonatal mice were subjected to hypoxia (5% oxygen for 120min) at postnatal day 1 and received NaHS (5.6mg/kg) once daily for 3d. Neurobehavioral toxicity was examined at 3-30d after hypoxia. Treatment with NaHS significantly attenuated the delayed development of sensory and motor reflexes induced by hypoxia up to two weeks after the insult. Moreover, NaHS improved the learning and memory performance of hypoxic animals as indicated in Morris water maze test at 30d after hypoxia. In mice exposed to hypoxia, treatment with NaHS enhanced expression of brain derived neurotrophic factor (BDNF) in the hippocampus. Furthermore, the protective effects of NaHS were associated with its ability to repress the hypoxia-induced nitric oxide synthase (NOS) activity and nitric oxide production in the hippocampus of mice brain. Taken together, these results suggest that the long-lasting beneficial effects of NaHS on hypoxia-induced neurobehavioral deficits are mediated, at least in part, by inducing BDNF expression and suppressing NOS activity in the brain of mice.

  12. Acidosis, hypoxia and bone.

    Science.gov (United States)

    Arnett, Timothy R

    2010-11-01

    Bone homeostasis is profoundly affected by local pH and oxygen tension. It has long been recognised that the skeleton contains a large reserve of alkaline mineral (hydroxyapatite), which is ultimately available to neutralise metabolic H(+) if acid-base balance is not maintained within narrow limits. Bone cells are extremely sensitive to the direct effects of pH: acidosis inhibits mineral deposition by osteoblasts but it activates osteoclasts to resorb bone and other mineralised tissues. These reciprocal responses act to maximise the availability of OH(-) ions from hydroxyapatite in solution, where they can buffer excess H(+). The mechanisms by which bone cells sense small pH changes are likely to be complex, involving ion channels and receptors in the cell membrane, as well as direct intracellular effects. The importance of oxygen tension in the skeleton has also long been known. Recent work shows that hypoxia blocks the growth and differentiation of osteoblasts (and thus bone formation), whilst strongly stimulating osteoclast formation (and thus bone resorption). Surprisingly, the resorptive function of osteoclasts is unimpaired in hypoxia. In vivo, tissue hypoxia is usually accompanied by acidosis due to reduced vascular perfusion and increased glycolytic metabolism. Thus, disruption of the blood supply can engender a multiple negative impact on bone via the direct actions of reduced pO(2) and pH on bone cells. These observations may contribute to our understanding of the bone disturbances that occur in numerous settings, including ageing, inflammation, fractures, tumours, anaemias, kidney disease, diabetes, respiratory disease and smoking.

  13. Description of 103 Cases of Hypobaric Sickness from NASA-sponsored Research

    Science.gov (United States)

    Conkin, Johnny; Klein, Jill S.; Acock, Keena E.

    2003-01-01

    One hundred and three cases of hypobaric decompression sickness (DCS) are documented, with 6 classified as Type II DCS. The presence and grade of venous gas emboli (VGE) are part of the case descriptions. Cases were diagnosed from 731 exposures in 5 different altitude chambers from 4 different laboratories between the years 1982 and 1999. Research was funded by NASA to develop operational prebreathe (PB) procedures that would permit safe extravehicular activity from the Space Shuttle and International Space Station using an extravehicular mobility unit (spacesuit) operated at 4.3 psia. Both vehicles operate at 14.7 psia with an "air" atmosphere, so a PB procedure is required to reduce nitrogen partial pressure in the tissues to an acceptable level prior to depressurization to 4.3 psia. Thirty-two additional descriptions of symptoms that were not diagnosed as DCS together with VGE information are also included. The information for each case resides in logbooks from 32 different tests. Additional information is stored in the NASA Decompression Sickness Database and the Prebreathe Reduction Protocol Database, both maintained by the Environmental Physiology Laboratory at the Johnson Space Center. Both sources were reviewed to provide the narratives that follow.

  14. Chronic hypoxia promotes pulmonary artery endothelial cell proliferation through H2O2-induced 5-lipoxygenase.

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    Kristi M Porter

    Full Text Available Pulmonary Hypertension (PH is a progressive disorder characterized by endothelial dysfunction and proliferation. Hypoxia induces PH by increasing vascular remodeling. A potential mediator in hypoxia-induced PH development is arachidonate 5-Lipoxygenase (ALOX5. While ALOX5 metabolites have been shown to promote pulmonary vasoconstriction and endothelial cell proliferation, the contribution of ALOX5 to hypoxia-induced proliferation remains unknown. We hypothesize that hypoxia exposure stimulates HPAEC proliferation by increasing ALOX5 expression and activity. To test this, human pulmonary artery endothelial cells (HPAEC were cultured under normoxic (21% O2 or hypoxic (1% O2 conditions for 24-, 48-, or 72 hours. In a subset of cells, the ALOX5 inhibitor, zileuton, or the 5-lipoxygenase activating protein inhibitor, MK-886, was administered during hypoxia exposure. ALOX5 expression was measured by qRT-PCR and western blot and HPAEC proliferation was assessed. Our results demonstrate that 24 and 48 hours of hypoxia exposure have no effect on HPAEC proliferation or ALOX5 expression. Seventy two hours of hypoxia significantly increases HPAEC ALOX5 expression, hydrogen peroxide (H2O2 release, and HPAEC proliferation. We also demonstrate that targeted ALOX5 gene silencing or inhibition of the ALOX5 pathway by pharmacological blockade attenuates hypoxia-induced HPAEC proliferation. Furthermore, our findings indicate that hypoxia-induced increases in cell proliferation and ALOX5 expression are dependent on H2O2 production, as administration of the antioxidant PEG-catalase blocks these effects and addition of H2O2 to HPAEC promotes proliferation. Overall, these studies indicate that hypoxia exposure induces HPAEC proliferation by activating the ALOX5 pathway via the generation of H2O2.

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

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    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.

  16. CD147 promotes melanoma progression through hypoxia-induced MMP2 activation.

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    Zeng, W; Su, J; Wu, L; Yang, D; Long, T; Li, D; Kuang, Y; Li, J; Qi, M; Zhang, J; Chen, X

    2014-01-01

    Hypoxia enhances MMP2 expression and the invasion and metastatic potential of melanoma cells. CD147 has been shown to induce MMP2 in multiple cancers. To investigate the role of CD147 in hypoxiainduced MMP2 activation, we performed immunohistochemistry (IHC) staining in 206 normal and melanoma tissue samples, and analyzed the correlation between HIF1α and CD147. ChIP (chromosome Immunoprecipitation) in melanoma cell lines supports that HIF1α directly binds to CD147 promoter. Moreover, we made a series of deletion mutants of CD147 promoter, and identified a conserved HIF1α binding site. Point mutation in this site significantly decreased CD147 response to hypoxia. Importantly, knocking down CD147 attenuates MMP2 response to hypoxia in melanoma cell lines. MMP2 could not be efficiently activated by hypoxia in CD147 depletion cells. ELISA data showed that MMP2 secretion was reduced in CD147 depletion cells than control under hypoxia condition. To verify the data from cell culture model, we performed in vivo mouse xenograft experiment. IHC staining showed reduced MMP2 level in CD147 depleted xenografts compared to the control group, with the HIF1α level being comparable. Our study demonstrates a novel pathway mediated by CD147 to promote the MMP2 activation induced by hypoxia, and helps to understand the interplay between hypoxia and melanoma progression.

  17. Effects of chloramphenicol preconditioning on oxidative respiratory function of cerebral mitochondria in rats exposed to acute hypoxia

    Institute of Scientific and Technical Information of China (English)

    陈丽峰; 柳君泽; 党永明; 宋熔

    2004-01-01

    Objective: To investigate the roles of chloramphenicol (CAP) preconditioning in the oxidative respiratory function of cerebral mitochondria in rats exposed to acute hypoxia during acute hypoxia by observing the changes of mitochondrial oxidative respiratory function and cytochrome C oxidase (COX) activity. Methods: Adult male Wistar rats were randomly divided into 4 groups: control (C), medication (M), hypoxia (H), and medication plus hypoxia (MH). Rats in groups M and MH were administered by peritoneal injection of CAP (50 mg/kg) every 12 h for 7 d before decapitation, but those in groups H and MH were exposed to a hypobaric chamber simulating 5 000 m high altitude for 24 h. The rat cerebral cortex was removed and mitochondria were isolated by centrifugation. Mitochondrial respiratory function and COX activity were measured by Clark oxygen electrode. Results: Compared with Group C, Group H showed significantly elevated state 4respiration (ST4), decreased state 3 respiration (ST3), and respiratory control rate (RCR) in mitochondrial respiration during acute hypoxic exposure. ST3 in Group MH was significantly lower than that in Group C, but was not significantly different from that in Groups H and M, while ST4 in Group MH was significantly lower than that in groups C and H. RCR in Group MH was higher than that in Group H, but lower than that in Group C. COX activity in Group H was significantly lower than that in Group C. In Group MH, COX activity increased and was higher than that in Group H, but was still lower than that in Group C. Conclusion: Acute hypoxic exposure could lead to mitochondrial respiratory dysfunction, suggesting that CAP preconditioning might be beneficial to the recovery of rat respiratory finction. The change of COX activity is consistent with that of mitochondrial respiratory function during acute hypoxic exposure and CAP-administration, indicating that COX plays an important role in oxidative phosphorylation function of mitochondria from

  18. Effects on the rabbit carotid body of stimulation by almitrine, natural high altitude, and experimental normobaric hypoxia.

    Science.gov (United States)

    Smith, P; Heath, D; Fitch, R; Hurst, G; Moore, D; Weitzenblum, E

    1986-06-01

    Rabbits were given intraperitoneal injections of almitrine in ascending doses for 5 weeks. They were compared with a control group and with a group of rabbits which had been exposed from birth to the natural hypobaric hypoxia found at Cerro de Pasco (433 m) in the Peruvian Andes. A further group of animals was placed in an experimental normobaric chamber for either 3 or 6 months to subject them to the same degree of hypoxia as that occurring in Cerro. The carotid bodies of the rabbits in all these groups were processed for light and electron microscopy, and examined both qualitatively and quantitatively. The carotid bodies in the group given almitrine showed no changes in their size or in the population of their glomic cells when compared with controls. In contrast, the carotid bodies of Peruvian rabbits were greatly enlarged with a disproportionate increase in the population of the light variant of chief cell. Rabbits from the hypoxic chamber also had enlarged carotid bodies but those killed after 3 months showed an increase in the dark variant of chief cell, whereas after 6 months this cell was reduced in number. There was also intense cytoplasmic vacuolation. Election microscopy confirmed these changes and revealed that dark cells had larger, more pleomorphic granules than the light variant. Vacuolation of the granules in light cells was most pronounced in Peruvian rabbits, but was uncommon in animals exposed to hypoxia for 3 months. We suggest that the dark cell responds to the early stages of hypoxia but later matures into the light variant of chief cell.

  19. Effect of intermittent hypoxia on the reproduction of rats exposed to high altitude in the Chilean Altiplano.

    Science.gov (United States)

    Cikutovic, Marcos; Fuentes, Nelson; Bustos-Obregón, Eduardo

    2009-01-01

    Environmental parameters such as the large day-night temperature differences, high light radiation, and low humidity may have a synergistic effect with low oxygen pressure. To evaluate the effects of the exposure to intermittent chronic hypobaric hypoxia (ICHH) in nature on rat reproduction, a group of rats was alternately moved to a location at 3400 meters over sea level (moml) for 7 days and returned the subsequent week to sea level; this procedure was repeated six times. Hematological and reproductive parameters were measured and analyzed. At the end of the experimental protocol, hematocrit and hemoglobin concentrations were significantly greater in the ICHH group compared to the control group (Nx) (p < 0.05). The diameter of the seminiferous tubule and the height of the spermatogenic epithelium in ICHH rats presented a significant decrease in relation to Nx rats (p < 0.05). Consequently, the number of epididymal spermatozoa in the experimental animals decreased compared to normal rats, with no evidence of recovery after 84 days. The offspring of the different matings between normal and hypoxic animals decreased proportionally to hypoxia exposure. The low oxygen and the changes in testicular temperature homeostasis would provide a novel local mechanism to explain the decrease in sperm cell production and the reduced number of puppies born. The alterations of the reproductive parameters of the hypoxic female, plus testicular injuries and diminished sperm in males, result in a significant decrease in the reproductive activity of the animals.

  20. Hypoxia and hypoxia-inducible factors in leukaemias

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    Margaux eDeynoux

    2016-02-01

    Full Text Available Despite huge improvements in the treatment of leukaemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukaemic stem cells (LSCs within the bone marrow, which are able to self-renew and therefore re-establish the full tumour. The marrow microenvironment contributes considerably in supporting the protection and development of leukaemic cells. LSCs share specific niches with normal haematopoietic stem cells with the niche itself being composed of a variety of cell types including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells and vascular cells. A hallmark of the haematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of HSCs. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor family. In solid tumours, it has been well-established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukaemia is not considered a solid tumour, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukaemic cell proliferation, differentiation and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumour suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukaemic development and therapeutic resistance, and to discuss the recent hypoxia-based strategies proposed to eradicate leukaemias.

  1. Protocol for a prospective, controlled, observational study to evaluate the influence of hypoxia on healthy volunteers and patients with inflammatory bowel disease: the Altitude IBD Study

    Science.gov (United States)

    Vavricka, Stephan; Ruiz, Pedro A; Scharl, Sylvie; Biedermann, Luc; Scharl, Michael; de Vallière, Cheryl; Lundby, Carsten; Wenger, Roland H; Held, Leonhard; Merz, Tobias M; Gassmann, Max; Lutz, Thomas; Kunz, Andres; Bron, Denis; Fontana, Adriano; Strauss, Laura; Weber, Achim; Fried, Michael; Rogler, Gerhard

    2017-01-01

    Introduction Inflammatory bowel disease (IBD) is a chronic intestinal disorder, often leading to an impaired quality of life in affected patients. The importance of environmental factors in the pathogenesis of IBD, including their disease-modifying potential, is increasingly recognised. Hypoxia seems to be an important driver of inflammation, as has been reported by our group and others. The aim of the study is to evaluate if hypoxia can alter disease activity of IBD measured by Harvey-Bradshaw Activity Index in Crohn's disease (increase to ≥5 points) and the partial Mayo Score for ulcerative colitis (increase to ≥2 points). To test the effects of hypoxia under standardised conditions, we designed a prospective and controlled investigation in healthy controls and patients with IBD in stable remission. Methods and analysis This is a prospective, controlled and observational study. Participants undergo a 3-hour exposure to hypoxic conditions simulating an altitude of 4000 metres above sea level (m.a.s.l.) in a hypobaric pressure chamber. Clinical parameters, as well as blood and stool samples and biopsies from the sigmoid colon are collected at subsequent time points. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Kanton Zurich (reference KEK-ZH-number 2013-0284). The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trials registration number NCT02849821; Pre-results. PMID:28057654

  2. Lung Oxidative Damage by Hypoxia

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    O. F. Araneda

    2012-01-01

    Full Text Available One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

  3. 西洋参茎叶总皂苷通过抑制过度内质网应激减轻大鼠心肌细胞缺氧/复氧损伤%Panax quinquefolium saponin attenuates hypoxia/reoxygenation injury in rat cardiomyocytes by inhibiting excessive endoplasmic reticulum stress

    Institute of Scientific and Technical Information of China (English)

    王琛; 李玉珍; 王晓礽; 吕振嵘; 史大卓; 刘秀华

    2012-01-01

    目的:观察西洋参茎叶总皂苷 (PQS) 对缺氧/复氧 (H/R) 心肌细胞的保护作用,并从内质网应激 (ERS)的角度探讨其分子机制.方法:建立心肌细胞缺氧/复氧 (H/R) 损伤模型,以台盼蓝染色法、乳酸脱氢酶活性以及流式细胞术检测细胞损伤及凋亡情况;以RT-PCR和Western blotting方法,检测ERS标志分子葡萄糖调节蛋白78 (GRP78)、钙网蛋白 (CRT)、C/EBP同源蛋白 (CHOP)、caspase-12及凋亡相关蛋白Bcl-2、Bax的表达.结果:和H/R组心肌细胞相比,PQS+H/R组:(1) 细胞凋亡率降低4.19% (P<0.05),存活率升高21.2% (P<0.05),LDH活性降低66.58% (P<0.05);(2) Bcl-2 mRNA和蛋白表达分别升高30.9%和48.0% (P<0.05),Bax mRNA和蛋白表达分别降低39.7%和48.4% (P<0.05);(3) GRP78 mRNA和蛋白表达分别降低61.6%和37.7% (P<0.05),CRT mRNA和蛋白表达分别降低35.7%和52.2% (P<0.05); CHOP mRNA和蛋白表达分别降低57.0%和51.7% (P<0.05);剪切后的caspase-12蛋白表达降低34.9% (P<0.05).结论:PQS可减轻H/R诱导的心肌细胞损伤,其机制是降低H/R诱导的GRP78、CRT mRNA和蛋白表达,抑制CHOP、caspase-12等内质网凋亡通路激活,从而抑制过度ERS介导的细胞凋亡.%AIM:To investigate the effect of Panax quinquefolium saponin ( PQS ) on hypoxia/reoxygenation injury and excessive endoplasmic reticulum stress ( ERS) in rat cardiomyocytes. METHODS:Cultured cardiomyocytes of neonatal Sprague - Dawley rats were used to establish hypoxia/reoxygenation ( H/R ) model. The cardioprotective effects of PQS were observed. The morphological changes, the activity of lactate dehydrogenase ( LDH ) and cell apoptosis were assessed. The mRNA and protein expression levels of glucose - regulated protein 78 ( GRP78 ), calreticulin ( CRT ), C/EBP homologous protein ( CHOP ), caspase - 12 and apoptosis - associated protein Bax and Bcl - 2 were determined by RT - PCR and Western blotting. RESULTS: Compared with H/R cardiomyocytes, PQS decreased the

  4. Influence of polyunsaturated fatty acid diet on the hemorrheological response to physical exercise in hypoxia.

    Science.gov (United States)

    Guezennec, C Y; Nadaud, J F; Satabin, P; Leger, F; Lafargue, P

    1989-08-01

    Several studies have shown that hemorrheological parameters are modified by physical exercise and exposure to altitude hypoxia. These changes result in a decrease in red cell deformability (RCD). Similarly, it has been shown that a daily dietary fish oil supplement increases RCD. The purpose of this study was to evaluate the influence of fish oil diet on RCD after exercise. Fourteen male subjects (19-38 years old) were divided into two groups. The first group ate a "standard diet" rich in saturated lipids; the second group received a daily amount of 6 g of MaxEPA fish oil for 6 weeks. Before the 6 weeks of experimental nutrition, and just after this period, both groups were submitted to two physical exercises of 1 h cycling at 70% of their VO2max. One test was performed at sea level, the other at a simulated altitude of 3000 m in a hypobaric chamber. Blood samples were drawn before and after exercise and used to evaluate: (1) RCD by filtration on polycarbonate membrane, (2) plasma viscosity, and (3) erythrocyte phospholipid composition. Energy charge of red cell was evaluated by ATP/AMP/ADP and two to three DPB assays. Gas liquid chromatography indicated an increase in n-3 PUFA membrane erythrocyte composition. In the control group, RCD decreased by an average of 53% after exercise under hypoxic conditions and was unchanged after the same exercise at sea level. MaxEPA diet suppresses the decrease in RCD observed after hypoxic exercise. These results indicate a decrease in RCD under the combined effects of exercise and hypoxia, which is prevented by 6 weeks of fish oil supplement.

  5. Pilot study: rapidly cycling hypobaric pressure improves pain after 5 days in adiposis dolorosa

    Directory of Open Access Journals (Sweden)

    Karen L Herbst

    2010-08-01

    Full Text Available Karen L Herbst1, Thomas Rutledge21Department of Medicine, University of California, San Diego, California, USA; 2Department of Psychiatry, University of California, San Diego, California, USAAbstract: Adiposis dolorosa (AD is a rare disorder of painful nodular subcutaneous fat ­accompanied by fatigue, difficulty with weight loss, inflammation, increased fluid in ­adipose ­tissue (lipedema and lymphedema, and hyperalgesia. Sequential compression relieves ­lymphedema pain; we therefore hypothesized that whole body cyclic pneumatic hypobaric compression may relieve pain in AD. To avoid exacerbating hyperalgesia, we utilized a touch-free method, which is delivered via a high-performance altitude simulator, the Cyclic Variations in Altitude ConditioningTM (CVACTM process. As a pilot study, 10 participants with AD completed pain and quality of life questionnaires before and after 20–40 minutes of CVAC process daily for 5 days. Participants lost weight (195.5 ± 17.6–193.8 ± 17.3 lb; P = 0.03, and bioimpedance significantly decreased (510 ± 36–490 ± 38 ohm; P = 0.01. There was a significant decrease in scores on the Pain Catastrophizing Scale (P = 0.039, in average (P = 0.002, highest (P = 0.029, lowest (P = 0.04, and current pain severity (P = 0.02 on the Visual Analogue Scale, but there was no change in pain quality by the McGill Pain Questionnaire. There were no significant changes in total and physical SF-36 scores, but the mental score improved significantly (P = 0.049. There were no changes in the Pain Disability Index or Pittsburgh Sleep Quality Index. These data present a potential, new, noninvasive means of treating pain in AD by whole body pneumatic compression as part of the CVAC process. Although randomized, controlled trials are needed to confirm these data, the CVAC process could potentially help in treating AD pain and other chronic pain disorders.Keywords: bioimpedance, chronic pain, lipedema

  6. FDG uptake, a surrogate of tumour hypoxia?

    NARCIS (Netherlands)

    Dierckx, Rudi Andre; de Wiele, Christophe Van

    2008-01-01

    Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceutic

  7. 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...

  8. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans.

    Science.gov (United States)

    Spilk, Samson; Herr, Michael D; Sinoway, Lawrence I; Leuenberger, Urs A

    2013-12-01

    Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P vasodilation and could be particularly relevant when other vasodilator systems are impaired.

  9. Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia

    Directory of Open Access Journals (Sweden)

    Mythen Monty G

    2010-10-01

    Full Text Available Abstract Background The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH. The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic associated with inter-individual variation in these responses. Methods Design Observational cohort study of progressive incremental exposure to EHH. Setting University human physiology laboratory in London, UK (75 m and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m. Participants 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC (5300 m. A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest. Main outcome measures Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation, allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry. Results Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m. All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude field measurements of exercise

  10. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    Science.gov (United States)

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  11. 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

  12. Dark Adaptation at High Altitude: An Unexpected Pupillary Response to Chronic Hypoxia in Andean Highlanders.

    Science.gov (United States)

    Healy, Katherine; Labrique, Alain B; Miranda, J Jaime; Gilman, Robert H; Danz, David; Davila-Roman, Victor G; Huicho, Luis; León-Velarde, Fabiola; Checkley, William

    2016-09-01

    Healy, Katherine, Alain B. Labrique, J. Jaime Miranda, Robert H. Gilman, David Danz, Victor G. Davila-Roman, Luis Huicho, Fabiola León-Velarde, and William Checkley. Dark adaptation at high altitude: an unexpected pupillary response to chronic hypoxia in Andean highlanders. High Alt Med Biol. 17:208-213, 2016.-Chronic mountain sickness is a maladaptive response to high altitude (>2500 m above sea level) and is characterized by excessive erythrocytosis and hypoxemia resulting from long-term hypobaric hypoxia. There is no known early predictor of chronic mountain sickness and the diagnosis is based on the presence of excessive erythrocytosis and clinical features. Impaired dark adaptation, or an inability to visually adjust from high- to low-light settings, occurs in response to mild hypoxia and may serve as an early predictor of hypoxemia and chronic mountain sickness. We aimed to evaluate the association between pupillary response assessed by dark adaptometry and daytime hypoxemia in resident Andean highlanders aged ≥35 years living in Puno, Peru. Oxyhemoglobin saturation (SpO2) was recorded using a handheld pulse oximeter. Dark adaptation was quantitatively assessed as the magnitude of pupillary contraction to light stimuli of varying intensities (-2.9 to 0.1 log-cd/m(2)) using a portable dark adaptometer. Individual- and stimulus-specific multilevel analyses were conducted using mixed-effect models to elicit the relationship between SpO2 and pupillary responsiveness. Among 93 participants, mean age was 54.9 ± 11.0 years, 48% were male, 44% were night blind, and mean SpO2 was 89.3% ± 3.4%. The magnitude of pupillary contraction was greater with lower SpO2 (p dark-adapted conditions was exaggerated with hypoxemia and may serve as an early predictor of chronic mountain sickness. This unexpected association is potentially explained as an excessive and unregulated sympathetic response to hypoxemia at altitude.

  13. Combined use of hyperbaric and hypobaric ropivacaine significantly improves hemodynamic characteristics in spinal anesthesia for caesarean section: a prospective, double-blind, randomized, controlled study.

    Directory of Open Access Journals (Sweden)

    ZheFeng Quan

    Full Text Available To observe the hemodynamic changes of parturients in the combined use of hyperbaric (4 mg and hypobaric (6 mg ropivacaine during spinal anesthesia for caesarean section in this randomized double-blind study.Parturients (n = 136 undergoing elective cesarean delivery were randomly and equally allocated to receive either combined hyperbaric and hypobaric ropivacaine (Group A or hyperbaric ropivacaine (Group B. Outcome measures were: hemodynamic characteristics, maximum height of sensory block, time to achieve T8 sensory blockade level, incidence of complications, Apgar scores at 1 and 5 min, and neonatal blood gas analysis.Group A had a lower level of sensory blockade (T6 [T6-T7] and longer time to achieve T8 sensory blockade level (8 ± 1.3 min than did patients in Group B (T3 [T2-T4] and 5 ± 1.0 min, respectively; P < 0.001, both. The incidence rates for hypotension, nausea, and vomiting were significantly lower in Group A (13%, 10%, and 3%, respectively than Group B (66%, 31%, and 13%; P < 0.001, P = 0.003, P = 0.028.Combined use of hyperbaric (4 mg and hypobaric (6 mg ropivacaine significantly decreased the incidences of hypotension and complications in spinal anesthesia for caesarean section by extending induction time and decreasing the level of sensory blockade.Chinese Clinical Trial Register ChiCTR-TRC-13004622.

  14. Ghrelin, GLP-1, and leptin responses during exposure to moderate hypoxia.

    Science.gov (United States)

    Morishima, Takuma; Goto, Kazushige

    2016-04-01

    Severe hypoxia has been indicated to cause acute changes in appetite-related hormones, which attenuate perceived appetite. However, the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite have not been elucidated. Therefore, we examined the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite. Eight healthy males (21.0 ± 0.6 years; 173 ± 2.3 cm; 70.6 ± 5.0 kg; 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial in normoxia (FiO2 = 20.9%) and a rest trial in hypoxia (FiO2 = 15.0%). The experimental trials were performed over 7 h in an environmental chamber. Blood samples and scores of subjective appetite were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after initiating exposure to hypoxia or normoxia within the chamber. Although each meal significantly reduced plasma active ghrelin concentrations (P ghrelin concentrations over 7 h were observed between the two trials. No significant differences were observed in glucagon-like peptide 1 or leptin concentrations over 7 h between the trials. The subjective feeling of hunger and fullness acutely changed in response to meal ingestions. However, these responses were not affected by exposure to moderate hypoxia. In conclusion, 7 h of exposure to moderate hypoxia did not change appetite-related hormonal responses or perceived appetite in healthy males.

  15. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.

    Science.gov (United States)

    Barsoum, Ivraym B; Smallwood, Chelsea A; Siemens, D Robert; Graham, Charles H

    2014-02-01

    Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

  16. Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses, and fungal pathogenesis

    Science.gov (United States)

    Grahl, Nora; Dinamarco, Taisa Magnani; Willger, Sven D.; Goldman, Gustavo H.; Cramer, Robert A.

    2012-01-01

    Summary We previously observed that hypoxia is an important component of host microenvironments during pulmonary fungal infections. However, mechanisms of fungal growth in these in vivo hypoxic conditions are poorly understood. Here, we report that mitochondrial respiration is active in hypoxia (1% oxygen) and critical for fungal pathogenesis. We generated Aspergillus fumigatus alternative oxidase (aoxA) and cytochrome C (cycA) null mutants and assessed their ability to tolerate hypoxia, macrophage killing, and virulence. In contrast to ΔaoxA, ΔcycA was found to be significantly impaired in conidia germination, growth in normoxia and hypoxia, and displayed attenuated virulence. Intriguingly, loss of cycA results in increased levels of AoxA activity, which results in increased resistance to oxidative stress, macrophage killing, and long-term persistence in murine lungs. Thus, our results demonstrate a previously unidentified role for fungal mitochondrial respiration in the pathogenesis of aspergillosis, and lay the foundation for future research into its role in hypoxia signaling and adaptation. PMID:22443190

  17. Hypoxia, Monitoring, and Mitigation System

    Science.gov (United States)

    2015-08-01

    22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply...unlimited. 13. SUPPLEMENTARY NOTES The original document contains color images . 14. ABSTRACT The Hypoxia Monitoring, Alert and Mitigation System...was started in May. Optional Tasks 3, 4 and 5 have not been exercised . The second iteration of the arm mounted prototype is being fabricated and tested

  18. Hypoxia Impairs Vasodilation in the Lung

    OpenAIRE

    Norbert F Voelkel; McMurtry, Ivan F.; Reeves, John T.

    1981-01-01

    Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation aft...

  19. Role of chronic hypoxia and hypoxia inducible factor in kidney disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Cells are endowed with a defensive mechanism against hypoxia,namely hypoxia-inducible factor (HIF) and hypoxia-responsive element (HRE).Under hypoxic conditions,activation of HIF leads to expression of a variety of adaptive genes with HRE in a coordinated manner.

  20. Brain dysfunction in mild to moderate hypoxia.

    Science.gov (United States)

    Gibson, G E; Pulsinelli, W; Blass, J P; Duffy, T E

    1981-06-01

    Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac pulmonary failure. The effects of acute graded hypoxia or higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.

  1. Cyclosporine Treatment Reduces Oxygen Free Radical Generation and Oxidative Stress in the Brain of Hypoxia-Reoxygenated Newborn Piglets

    Science.gov (United States)

    Liu, Jiang-Qin; Chaudhary, Hetal; Brocks, Dion R.; Bigam, David L.; Cheung, Po-Yin

    2012-01-01

    Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H2O2) production and markers of oxidative stress. Piglets (1–4 d, 1.4–2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation)(n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40–48% of baseline), hypotension (mean arterial pressure 27–31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H2O2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H2O2 production and minimizes oxidative stress in newborn piglets following hypoxia

  2. Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

    Directory of Open Access Journals (Sweden)

    Richdeep S Gill

    Full Text Available Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H(2O(2 production and markers of oxidative stress. Piglets (1-4 d, 1.4-2.5 kg were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation (n = 8/group. At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls or cyclosporine (2.5 or 10 mg/kg i.v. bolus in a blinded-randomized fashion. An additional sham-operated group (n = 4 underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe, cerebral cortical H(2O(2 production (electrochemical sensor, cerebral tissue glutathione (ELISA and cytosolic cytochrome-c (western blot levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40-48% of baseline, hypotension (mean arterial pressure 27-31 mmHg and acidosis (pH 7.04 at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg, significantly attenuated the increase in cortical H(2O(2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H(2O(2 production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

  3. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

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

    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...... analysis for PET imaging of hypoxia....

  4. A trihelix DNA binding protein counterbalances hypoxia-responsive transcriptional activation in Arabidopsis.

    Science.gov (United States)

    Giuntoli, Beatrice; Lee, Seung Cho; Licausi, Francesco; Kosmacz, Monika; Oosumi, Teruko; van Dongen, Joost T; Bailey-Serres, Julia; Perata, Pierdomenico

    2014-09-01

    Transcriptional activation in response to hypoxia in plants is orchestrated by ethylene-responsive factor group VII (ERF-VII) transcription factors, which are stable during hypoxia but destabilized during normoxia through their targeting to the N-end rule pathway of selective proteolysis. Whereas the conditionally expressed ERF-VII genes enable effective flooding survival strategies in rice, the constitutive accumulation of N-end-rule-insensitive versions of the Arabidopsis thaliana ERF-VII factor RAP2.12 is maladaptive. This suggests that transcriptional activation under hypoxia that leads to anaerobic metabolism may need to be fine-tuned. However, it is presently unknown whether a counterbalance of RAP2.12 exists. Genome-wide transcriptome analyses identified an uncharacterized trihelix transcription factor gene, which we named HYPOXIA RESPONSE ATTENUATOR1 (HRA1), as highly up-regulated by hypoxia. HRA1 counteracts the induction of core low oxygen-responsive genes and transcriptional activation of hypoxia-responsive promoters by RAP2.12. By yeast-two-hybrid assays and chromatin immunoprecipitation we demonstrated that HRA1 interacts with the RAP2.12 protein but with only a few genomic DNA regions from hypoxia-regulated genes, indicating that HRA1 modulates RAP2.12 through protein-protein interaction. Comparison of the low oxygen response of tissues characterized by different levels of metabolic hypoxia (i.e., the shoot apical zone versus mature rosette leaves) revealed that the antagonistic interplay between RAP2.12 and HRA1 enables a flexible response to fluctuating hypoxia and is of importance to stress survival. In Arabidopsis, an effective low oxygen-sensing response requires RAP2.12 stabilization followed by HRA1 induction to modulate the extent of the anaerobic response by negative feedback regulation of RAP2.12. This mechanism is crucial for plant survival under suboptimal oxygenation conditions. The discovery of the feedback loop regulating the oxygen

  5. Paeoniflorin prevents hypoxia-induced epithelial–mesenchymal transition in human breast cancer cells

    Directory of Open Access Journals (Sweden)

    Zhou Z

    2016-04-01

    Full Text Available Zhenyu Zhou,1,* Shunchang Wang,1,* Caijuan Song,2 Zhuang Hu11Department of Thyroid and Breast, Huaihe Hospital, Henan University, Kaifeng, 2Department of Immunization Program, Zhengzhou Center for Disease Control and Prevention, Zhengzhou, People’s Republic of China*These authors contributed equally to this workAbstract: Paeoniflorin (PF is a monoterpene glycoside extracted from the root of Paeonia lactiflora Pall. Previous studies have demonstrated that PF inhibits the growth, invasion, and metastasis of tumors in vivo and in vitro. However, the effect of PF on hypoxia-induced epithelial–mesenchymal transition (EMT in breast cancer cells remains unknown. Therefore, the objective of this study was to investigate the effect of PF on hypoxia-induced EMT in breast cancer cells, as well as characterize the underlying mechanism. The results presented in this study demonstrate that PF blocks the migration and invasion of breast cancer cells by repressing EMT under hypoxic conditions. PF also significantly attenuated the hypoxia-induced increase in HIF-1α level. Furthermore, PF prevented hypoxia-induced expression of phosphorylated PI3K and Akt in MDA-MB-231 cells. In conclusion, PF prevented hypoxia-induced EMT in breast cancer cells by inhibiting HIF-1α expression via modulation of PI3K/Akt signaling pathway. This finding provides evidence that PF can serve as a therapeutic agent for the treatment of breast cancer.Keywords: paeoniflorin, breast cancer, hypoxia, epithelial–mesenchymal transition, PI3K/Akt signaling pathway

  6. Hypoxia: Exposure Time Until Significant Performance Effects

    Science.gov (United States)

    2016-03-07

    and self-reported symptoms. Additionally, the PowerLab computer system interfaced with the gas analyzer to measure levels of carbon dioxide (CO2) and...processing by hypoxia. Ergonomics , 36(6), 727-35. 4. Fowler, B., Elcombe, D.D., Kelso, B., & Porlier, G. (1987). The threshold for hypoxia effects on... Ergonomics , 25(3), 189-201. 9. Gold, R.E. & Kulak, L.L. (1972). Effect of hypoxia on aircraft pilot performance. Aerospace Medicine, 43(2), 180-3

  7. Hypoxia-induced 15-HETE enhances the constriction of internal carotid arteries by down-regulating potassium channels.

    Science.gov (United States)

    Zhu, Yanmei; Chen, Li; Liu, Wenjuan; Wang, Weizhi; Zhu, Daling; Zhu, Yulan

    2010-08-15

    Severe hypoxia induces the constriction of internal carotid arteries (ICA), which worsens ischemic stroke in the brain. A few metabolites are presumably involved in hypoxic vasoconstriction, however, less is known about how such molecules provoke this vasoconstriction. We have investigated the influence of 15-hydroxyeicosatetrienoic acid (15-HETE) produced by 15-lipoxygenase (15-LOX) on vasoconstriction during hypoxia. As showed in our results, 15-LOX level increases in ICA endothelia and smooth muscles. 15-HETE enhances the tension of ICA ring in a dose-dependent manner, as well as attenuates the activities and expression of voltage-gated potassium channels (Kv 1.5 and Kv 2.1). Therefore, the down-regulation of Kv channels by 15-HETE during hypoxia may weaken the repolarization of action potentials and causes a dominant influx of calcium ions to enhance smooth muscle tension and ICA constriction.

  8. Baicalin Inhibits Hypoxia-Induced Pulmonary Artery Smooth Muscle Cell Proliferation via the AKT/HIF-1α/p27-Associated Pathway

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    2014-05-01

    Full Text Available 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.

  9. Photonic Crystal Fiber Attenuator

    Institute of Scientific and Technical Information of China (English)

    Joo; Beom; Eom; Hokyung; Kim; Jinchae; Kim; Un-Chul; Paek; Byeong; Ha; Lee

    2003-01-01

    We propose a novel fiber attenuator based on photonic crystal fibers. The difference in the modal field diameters of a conventional single mode fiber and a photonic crystal fiber was used. A variable optical attenuator was also achieved by applying macro-bending on the PCF part of the proposed attenuator

  10. 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...

  11. 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...

  12. Triptolide protects astrocytes from hypoxia/ reoxygenation injury

    Institute of Scientific and Technical Information of China (English)

    Minfang Guo; Hongcui Fan; Jiezhong Yu; Ning Ji; Yongsheng Sun; Liyun Liang; Baoguo Xiao; Cungen Ma

    2011-01-01

    Astrocytes in an in vitro murine astrocyte model of oxygen and glucose deprivation/hypoxia and reoxygenation were treated with different concentrations of triptolide (250, 500, 1 000 ng/mL) in a broader attempt to elucidate the protection and mechanism underlying triptolide treatment on astrocytes exposed to hypoxia/reoxygenation injury. The results showed that the matrix metalloproteinase-9, interleukin-1β, tumor necrosis factor α and interleukin-6 expressions were significantly decreased after triptolide treatment in the astrocytes exposed to hypoxia/ reoxygenation injury, while interleukin-10 expression was upregulated. In addition, the vitality of the injured astrocytes was enhanced, the triptolide's effect was apparent at 500 ng/mL. These experimental findings indicate that triptolide treatment could protect astrocytes against hypoxia/ reoxygenation injury through the inhibition of inflammatory response and the reduction of matrix metalloproteinase-9 expression.

  13. 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...

  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. 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...

  16. 2006 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. 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...

  18. 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.

  19. Tracer attenuation in groundwater

    Science.gov (United States)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  20. Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.

    Science.gov (United States)

    Carlsson, Ylva; Leverin, Anna-Lena; Hedtjärn, Maj; Wang, Xiaoyang; Mallard, Carina; Hagberg, Henrik

    2009-01-01

    Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.

  1. Sensing and surviving hypoxia in vertebrates.

    Science.gov (United States)

    Jonz, Michael G; Buck, Leslie T; Perry, Steve F; Schwerte, Thorsten; Zaccone, Giacomo

    2016-02-01

    Surviving hypoxia is one of the most critical challenges faced by vertebrates. Most species have adapted to changing levels of oxygen in their environment with specialized organs that sense hypoxia, while only few have been uniquely adapted to survive prolonged periods of anoxia. The goal of this review is to present the most recent research on oxygen sensing, adaptation to hypoxia, and mechanisms of anoxia tolerance in nonmammalian vertebrates. We discuss the respiratory structures in fish, including the skin, gills, and air-breathing organs, and recent evidence for chemosensory neuroepithelial cells (NECs) in these tissues that initiate reflex responses to hypoxia. The use of the zebrafish as a genetic and developmental model has allowed observation of the ontogenesis of respiratory and chemosensory systems, demonstration of a putative intracellular O2 sensor in chemoreceptors that may initiate transduction of the hypoxia signal, and investigation into the effects of extreme hypoxia on cardiorespiratory development. Other organisms, such as goldfish and freshwater turtles, display a high degree of anoxia tolerance, and these models are revealing important adaptations at the cellular level, such as the regulation of glutamatergic and GABAergic neurotransmission in defense of homeostasis in central neurons.

  2. 低压条件下梨枣和番茄乙烯的变化%Effects of Hypobaric Condition on Ethylene Changes in Lizao Jujube and Tomato Fruit

    Institute of Scientific and Technical Information of China (English)

    石建春; 王如福

    2011-01-01

    以梨枣和番茄为试材,研究了2种果实在低压贮藏过程中组织内乙烯和乙烯释放量的变化.结果表明,低压可有效抑制梨枣和番茄组织内乙烯的产生,减少组织内乙烯的积累;梨枣和番茄在低压条件下的乙烯释放量低于常压;低压可推迟番茄乙烯高峰的出现,降低乙烯峰值,并且能有效延缓梨枣和番茄的成熟与衰老.%Lizao jujube and tomato were used to investigate the change of internal ethylene and ethylene release in condition of hypobaric. The results of the study showed that hypobaric storage could significantly inhibit internal ethylene production, reduce internal ethylene concentration and ethylene release of hypobaric storage were less than that of CK, and it also could postpone the appearing time of tomato's ethylene peak and degrade value of the peak. Thus the experiment showed that hypobaric storage could effectively delay ripening and senescence of Lizao jujube and tomato fruit.

  3. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    BACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase\\/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.

  4. Changes in carotid body and nTS neuronal excitability following neonatal sustained and chronic intermittent hypoxia exposure.

    Science.gov (United States)

    Mayer, C A; Wilson, C G; MacFarlane, P M

    2015-01-01

    We investigated whether pre-treatment with neonatal sustained hypoxia (SH) prior to chronic intermittent hypoxia (SH+CIH) would modify in vitro carotid body (CB) chemoreceptor activity and the excitability of neurons in the caudal nucleus of the solitary tract (nTS). Sustained hypoxia followed by CIH exposure simulates an oxygen paradigm experienced by extremely premature infants who developed persistent apnea. Rat pups were treated with 5 days of SH (11% O2) from postnatal age 1 (P1) followed by 10 days of subsequent chronic intermittent hypoxia (CIH, 5% O2/5 min, 8 h/day, between P6 and P15) as described previously (Mayer et al., Respir. Physiol. Neurobiol. 187(2): 167-75, 2013). At the end of SH+CIH exposure (P16), basal firing frequency was enhanced, and the hypoxic sensory response of single unit CB chemoafferents was attenuated. Further, basal firing frequency and the amplitude of evoked excitatory post-synaptic currents (ESPC's) of nTS neurons was augmented compared to age-matched rats raised in normoxia. These effects were unique to SH+CIH exposure as neither SH or CIH alone elicited any comparable effect on chemoafferent activity or nTS function. These data indicated that pre-treatment with neonatal SH prior to CIH exposure uniquely modified mechanisms of peripheral (CB) and central (nTS) neural function in a way that would be expected to disturb the ventilatory response to acute hypoxia.

  5. Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4

    LENUS (Irish Health Repository)

    Cronin, Patricia A

    2010-05-21

    Abstract Background Chemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α. Methods Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability. Results CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α in vitro. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness. Conclusions CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.

  6. Impact of exercise and moderate hypoxia on glycemic regulation and substrate oxidation pattern.

    Directory of Open Access Journals (Sweden)

    Takuma Morishima

    Full Text Available OBJECTIVE: We examined metabolic and endocrine responses during rest and exercise in moderate hypoxia over a 7.5 h time courses during daytime. METHODS: Eight sedentary, overweight men (28.6 ± 0.8 kg/m2 completed four experimental trials: a rest trial in normoxia (FiO2 = 20.9%, NOR-Rest, an exercise trial in normoxia (NOR-Ex, a rest trial in hypoxia (FiO2 = 15.0%, HYP-Rest, and an exercise trial in hypoxia (HYP-Ex. Experimental trials were performed from 8:00 to 15:30 in an environmental chamber. Blood and respiratory gas samples were collected over 7.5 h. In the exercise trials, subjects performed 30 min of pedaling exercise at 60% of VO2max at 8:00, 10:30, and 13:00, and rested during the remaining period in each environment. Standard meals were provided at 8:30, 11:00, and 13:30. RESULTS: The areas under the curves for blood glucose and serum insulin concentrations over 7.5 h did not differ among the four trials. At baseline, %carbohydrate contribution was significantly higher in the hypoxic trials than in the normoxic trials (P<0.05. Although exercise promoted carbohydrate oxidation in the NOR-Ex and HYP-Ex trials, %carbohydrate contribution during each exercise and post-exercise period were significantly higher in the HYP-Ex trial than in the NOR-Ex trial (P<0.05. CONCLUSION: Three sessions of 30 min exercise (60% of VO2max in moderate hypoxia over 7.5 h did not attenuate postprandial glucose and insulin responses in young, overweight men. However, carbohydrate oxidation was significantly enhanced when the exercise was conducted in moderate hypoxia.

  7. NOTCH SIGNALLING MODULATES HYPOXIA-INDUCED NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CANCER CELLS

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-01-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation has been associated with tumor progression, poor prognosis and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavourable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells, in vitro. Results exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent down regulation of Notch-mediated signalling, as demonstrated by reduced levels of the Notch target genes, Hes1 and Hey1. Neuroendocrine differentiation was promoted by attenuation of Hes1 transcription, as cells expressing a dominant negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia down regulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen independent cell lines, PC3 and Du145, it did not change the extent of NE differentiation in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions hypoxia induces neuroendocrine differentiation of LNCaP cells in vitro, which appears to be driven by the inhibition of Notch signalling with subsequent down-regulation of Hes1 transcription. PMID:22172337

  8. Hypoxia inducible factor 1α promotes survival of mesenchymal stem cells under hypoxia

    Science.gov (United States)

    Lv, Bingke; Li, Feng; Fang, Jie; Xu, Limin; Sun, Chengmei; Han, Jianbang; Hua, Tian; Zhang, Zhongfei; Feng, Zhiming; Jiang, Xiaodan

    2017-01-01

    Mesenchymal stem cells (MSCs) are ideal materials for cell therapy. Research has indicated that hypoxia benefits MSC survival, but little is known about the underlying mechanism. This study aims to uncover potential mechanisms involving hypoxia inducible factor 1α (HIF1A) to explain the promoted MSC survival under hypoxia. MSCs were obtained from Sprague-Dawley rats and cultured under normoxia or hypoxia condition. The overexpression vector or small interfering RNA of Hif1a gene was transfected to MSCs, after which cell viability, apoptosis and expression of HIF1A were analyzed by MTT assay, flow cytometry, qRT-PCR and Western blot. Factors in p53 pathway were detected to reveal the related mechanisms. Results showed that hypoxia elevated MSCs viability and up-regulated HIF1A (P cell CLL/lymphoma 2 (BCL2) expression had the opposite pattern (P cell therapy.

  9. Hypoxia-on-a-chip

    Directory of Open Access Journals (Sweden)

    Busek Mathias

    2016-09-01

    Full Text Available In this work a microfluidic cell cultivation device for perfused hypoxia assays as well as a suitable controlling unit are presented. The device features active components like pumps for fluid actuation and valves for fluid direction as well as an oxygenator element to ensure a sufficient oxygen transfer. It consists of several individually structured layers which can be tailored specifically to the intended purpose. Because of its clearness, its mechanical strength and chemical resistance as well as its well-known biocompatibility polycarbonate was chosen to form the fluidic layers by thermal diffusion bonding. Several oxygen sensing spots are integrated into the device and monitored with fluorescence lifetime detection. Furthermore an oxygen regulator module is implemented into the controlling unit which is able to mix different process gases to achieve a controlled oxygenation. First experiments show that oxygenation/deoxygenation of the system is completed within several minutes when pure nitrogen or air is applied to the oxygenator. Lastly the oxygen input by the pneumatically driven micro pump was quantified by measuring the oxygen content before and after the oxygenator.

  10. Preparation and Preservation of Hypoxia UW Solution

    Institute of Scientific and Technical Information of China (English)

    WAN Chidang; WANG Chunyou; LIU Tan; CHENG Rui; YANG Zhiyong

    2007-01-01

    In order to explore the method to prepare hypoxia UW solution and the stability and preservation of hypoxia UW solution, UW solution was purged by argon or air for 15 min or 60 at a flow rate of 0.8 or 2 L/min, and the oxygen partial pressure of UW solution was detected. The hy-poxia UW solution was exposed to the air or sealed up to preserve by using different methods, and the changes of oxygen partial pressure was tested. The results showed that oxygen partial pressure of 50 mL UW solution, purged by argon for 15 min at a flow rate of 2 L/min, was declined from 242±6 mmHg to 83±10 mmHg. After exposure to the air, oxygen partial pressure of hypoxia UW solution was gradually increased to 160±7 mmHg at 48 h. After sealed up by the centrifuge tube and plastic bad filled with argon, oxygen partial pressure of hypoxia UW solution was stable, about 88±13 mmHg at 72 h. It was concluded that oxygen of UW solution could be purged by argon efficiently. Sealed up by the centrifuge tube and plastic bag filled with argon, oxygen partial pressure of UW so- lution could be stabilized.

  11. Hypoxia-regulated target genes implicated in tumor metastasis

    Directory of Open Access Journals (Sweden)

    Tsai Ya-Ping

    2012-12-01

    Full Text Available Abstract Hypoxia is an important microenvironmental factor that induces cancer metastasis. Hypoxia/hypoxia-inducible factor-1α (HIF-1α regulates many important steps of the metastatic processes, especially epithelial-mesenchymal transition (EMT that is one of the crucial mechanisms to cause early stage of tumor metastasis. To have a better understanding of the mechanism of hypoxia-regulated metastasis, various hypoxia/HIF-1α-regulated target genes are categorized into different classes including transcription factors, histone modifiers, enzymes, receptors, kinases, small GTPases, transporters, adhesion molecules, surface molecules, membrane proteins, and microRNAs. Different roles of these target genes are described with regards to their relationship to hypoxia-induced metastasis. We hope that this review will provide a framework for further exploration of hypoxia/HIF-1α-regulated target genes and a comprehensive view of the metastatic picture induced by hypoxia.

  12. AMP-Activated Protein Kinase α2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1α and a Network of Proteins Affecting Metabolism and Apoptosis

    Science.gov (United States)

    Abdel Malik, Randa; Zippel, Nina; Frömel, Timo; Heidler, Juliana; Zukunft, Sven; Walzog, Barbara; Ansari, Nariman; Pampaloni, Francesco; Wingert, Susanne; Rieger, Michael A.; Wittig, Ilka; Fisslthaler, Beate

    2017-01-01

    Rationale: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPKα1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKα2 subunit in vascular repair. Objective: To determine the role of the AMPKα2 subunit in vascular repair. Methods and Results: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKα2−/− versus wild-type mice, a phenotype reproduced in mice lacking AMPKα2 in myeloid cells (AMPKα2ΔMC). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPKα2ΔMC mice was lower than that in wild-type mice despite being higher after 24 hours. Neutrophil survival in ischemic tissue is required to attract monocytes that contribute to the angiogenic response. Indeed, apoptosis was increased in hypoxic neutrophils from AMPKα2ΔMC mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPKα2ΔMC hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1α induction was attenuated in AMPKα2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPKα2ΔMC mice. Mechanistically, isocitrate dehydrogenase expression and the production of α-ketoglutarate, which negatively regulate hypoxia-inducible factor-1α stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPKα2ΔMC mice. Conclusions: AMPKα2 regulates α-ketoglutarate generation, hypoxia-inducible factor-1α stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPKα2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia. PMID:27777247

  13. SpO2 and Heart Rate During a Real Hike at Altitude Are Significantly Different than at Its Simulation in Normobaric Hypoxia

    Science.gov (United States)

    Netzer, Nikolaus C.; Rausch, Linda; Eliasson, Arn H.; Gatterer, Hannes; Friess, Matthias; Burtscher, Martin; Pramsohler, Stephan

    2017-01-01

    Rationale: Exposures to simulated altitude (normobaric hypoxia, NH) are frequently used in preparation for mountaineering activities at real altitude (hypobaric hypoxia, HH). However, physiological responses to exercise in NH and HH may differ. Unfortunately clinically useful information on such differences is largely lacking. This study therefore compared exercise responses between a simulated hike on a treadmill in NH and a similar field hike in HH. Methods: Six subjects (four men) participated in two trials, one in a NH chamber and a second in HH at an altitude of 4,205 m on the mountain Mauna Kea. Subjects hiked in each setting for 7 h including breaks. In NH, hiking was simulated by walking on a treadmill. To achieve maximal similarity between hikes, subjects used the same nutrition, clothes, and gear weight. Measurements of peripheral oxygen saturation (SpO2), heart rate (HR) and barometrical pressure (PB)/inspired oxygen fraction (FiO2) were taken every 15 min. Acute mountain sickness (AMS) symptoms were assessed using the Lake-Louise-Score at altitudes of 2,800, 3,500, and 4,200 m. Results: Mean SpO2 values of 85.8% in NH were significantly higher compared to those of 80.2% in HH (p = 0.027). Mean HR values of 103 bpm in NH were significantly lower than those of 121 bpm in HH (p = 0.029). AMS scores did not differ significantly between the two conditions. Conclusion: Physiological responses to exercise recorded in NH are different from those provoked by HH. These findings are of clinical importance for subjects using simulated altitude to prepare for activity at real altitude. Trial registration: Registration at DRKS. (Approval No. 359/12, Trial No. DRKS00005241). PMID:28243206

  14. Rat reaction to hypokinesia after prior adaptation to hypoxia

    Science.gov (United States)

    Barashova, Z. I.; Tarakanova, O. I.

    1980-01-01

    The effect of prior hypoxia adaptation on body tolerance to hypokinesia was investigated. Rats trained to a 50 day period of hypokinesia and hypoxia with a preliminary month of adaptation to hypoxia showed less weight loss, higher indices for red blood content, heightened reactivity of the overall organism and the central nervous system to acute hypoxia, and decreased modification of the skeletal muscles compared to rats subjected to hypokinesia alone.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

    Full Text Available BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

  17. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

    Among vertebrates able to tolerate periods of oxygen deprivation, the painted and red-eared slider turtles (Chrysemys picta and Trachemys scripta) and the crucian carp (Carassius carassius) are the most extreme and can survive even months of total lack of oxygen during winter. The key to hypoxia ...... of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals....... survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and – in air breathing animals - redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite...... nitrite. The aim of this review is to highlight recent work illustrating the widespread roles of NO and nitrite in the tolerance to extreme oxygen deprivation, in particular in the red-eared slider turtle and crucian carp, but also in diving marine mammals. The emerging picture underscores the importance...

  18. Reductions in carotid chemoreceptor activity with low-dose dopamine improves baroreflex control of heart rate during hypoxia in humans.

    Science.gov (United States)

    Mozer, Michael T; Holbein, Walter W; Joyner, Michael J; Curry, Timothy B; Limberg, Jacqueline K

    2016-07-01

    The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of heart rate with exposure to hypoxia. We hypothesized spontaneous cardiac baroreflex sensitivity (scBRS) would be reduced with hypoxia and this effect would be blunted when carotid chemoreceptor activity was reduced with low-dose dopamine. Fifteen healthy adults (11 M/4 F) completed two visits randomized to intravenous dopamine or placebo (saline). On each visit, subjects were exposed to 5-min normoxia (~99% SpO2), followed by 5-min hypoxia (~84% SpO2). Blood pressure (intra-arterial catheter) and heart rate (ECG) were measured continuously and scBRS was assessed by spectrum and sequence methodologies. scBRS was reduced with hypoxia (P dopamine (P dopamine (P dopamine did not attenuate the decrease in baroreflex sensitivity to falling pressures (scBRS "down-down"; P > 0.05). Present findings are consistent with a reduction in scBRS with systemic hypoxia. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when activity of the chemoreceptors is reduced with low-dose dopamine. However, the improvement in scBRS with dopamine appears to be specific to rising blood pressures. These results may have important implications for impairments in baroreflex function common in disease states of acute and/or chronic hypoxemia, as well as the experimental use of dopamine to assess such changes.

  19. Measuring and monitoring eutrophication and hypoxia

    Digital Repository Service at National Institute of Oceanography (India)

    Naqvi, S.W.A.; Heidemeier, J.

    stream_size 16126 stream_content_type text/plain stream_name Hypoxia_Nutrient_Reduct_Coast_Zone_2011_27.pdf.txt stream_source_info Hypoxia_Nutrient_Reduct_Coast_Zone_2011_27.pdf.txt Content-Encoding UTF-8 Content-Type text... by legal (individual licensing stipulating requirement or restrictions) and technical measures (building or upgrading of treatment plants, changing production practices). In many highly susceptible areas, such as the Bay of Bengal and Andaman Sea...

  20. Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

    Directory of Open Access Journals (Sweden)

    Ying Xia

    2013-07-01

    Full Text Available We investigated whether δ-opioid receptor (DOR-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen for 1–10 days. The results showed that: (1 1-day hypoxia had no appreciable effect on BDNF expression, while 3- and 10-day hypoxia progressively decreased BDNF expression, resulting in 37.3% reduction (p < 0.05 after 10-day exposure; (2 DOR activation with UFP-512 (1 mg/kg, i.p., daily partially reversed the hypoxia-induced reduction of BDNF expression in the 3- or 10-day exposed cortex; (3 DOR activation partially reversed the hypoxia-induced reduction in functional TrkB (140-kDa and attenuated hypoxia-induced increase in truncated TrkB (90-kDa in the 3- or 10-day hypoxic cortex; and (4 prolonged hypoxia (10 days significantly increased TNF-α level and decreased CD11b expression in the cortex, which was completely reversed following DOR activation; and (5 there was no significant change in pCREB and pATF-1 levels in the hypoxic cortex. We conclude that prolonged hypoxia down-regulates BDNF-TrkB signaling leading to an increase in TNF-α in the cortex, while DOR activation up-regulates BDNF-TrkB signaling thereby decreasing TNF-α levels in the hypoxic cortex.

  1. 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.

  2. Hypoxia-induced hypothermia mediated by the glutamatergic transmission in the lateral preoptic area.

    Science.gov (United States)

    Osaka, T

    2012-12-13

    Hypoxia evokes a regulated decrease in the body core temperature, which response is mediated, at least in part, by noradrenaline (NA) and nitric oxide (NO) in the rostromedial preoptic area (POA) of the hypothalamus. In the accompanying paper, it was shown that glutamatergic activation of the lateral POA also evokes hypothermic responses. Here, I tested the hypothesis that the glutamatergic transmission in the lateral POA is critically involved in the neural mechanism of hypoxia-induced hypothermia. Hypoxic ventilation (10% O(2)-90% N(2), 5 min) as well as a single microinjection of NA (50 pmol) or the NO donor sodium nitroprusside (8.4 nmol) into the rostromedial POA evoked an increase in the tail skin temperature and a decrease in the colonic temperature in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. All of these responses were greatly attenuated by pretreatment with multiple microinjections of kynurenic acid (10 nmol, four locations), a nonselective glutamate receptor antagonist, but not by those with saline solution, in the bilateral rostral and central parts of the lateral POA. These results suggest that the NA- and NO-sensitive structure in the rostromedial POA activated the glutamatergic transmission in the lateral POA to mediate hypoxia-induced hypothermia.

  3. 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

  4. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    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.

  5. 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 cont

  6. 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...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...... (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...

  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

    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...... 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...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...

  8. Landing gear noise attenuation

    Science.gov (United States)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  9. MURC deficiency in smooth muscle attenuates pulmonary hypertension

    Science.gov (United States)

    Nakanishi, Naohiko; Ogata, Takehiro; Naito, Daisuke; Miyagawa, Kotaro; Taniguchi, Takuya; Hamaoka, Tetsuro; Maruyama, Naoki; Kasahara, Takeru; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling. PMID:27546070

  10. Ginsenoside Rb1 attenuates activated microglia-induced neuronal damage

    Institute of Scientific and Technical Information of China (English)

    Lining Ke; Wei Guo; Jianwen Xu; Guodong Zhang; Wei Wang; Wenhua Huang

    2014-01-01

    The microglia-mediated inlfammatory reaction promotes neuronal damage under cerebral isch-emia/hypoxia conditions. We therefore speculated that inhibition of hypoxia-induced microglial activation may alleviate neuronal damage. To test this hypothesis, we co-cultured ginsenoside Rb1, an active component of ginseng, and cortical neurons. Ginsenoside Rb1 protected neuronal morphology and structure in a single hypoxic culture system and in a hypoxic co-culture system with microglia, and reduced neuronal apoptosis and caspase-3 production. The protective effect was observable prior to placing in co-culture. Additionally, ginsenoside Rb1 inhibited levels of tumor necrosis factor-αin a co-culture system containing activated N9 microglial cells. Ginse-noside Rb1 also signiifcantly decreased nitric oxide and superoxide production induced by N9 microglia. Our ifndings indicate that ginsenoside Rb1 attenuates damage to cerebral cortex neu-rons by downregulation of nitric oxide, superoxide, and tumor necrosis factor-αexpression in hypoxia-activated microglia.

  11. The hypoxia signaling pathway and hypoxic adaptation in fishes.

    Science.gov (United States)

    Xiao, Wuhan

    2015-02-01

    The hypoxia signaling pathway is an evolutionarily conserved cellular signaling pathway present in animals ranging from Caenorhabditis elegans to mammals. The pathway is crucial for oxygen homeostasis maintenance. Hypoxia-inducible factors (HIF-1α and HIF-2α) are master regulators in the hypoxia signaling pathway. Oxygen concentrations vary a lot in the aquatic environment. To deal with this, fishes have adapted and developed varying strategies for living in hypoxic conditions. Investigations into the strategies and mechanisms of hypoxia adaptation in fishes will allow us to understand fish speciation and breed hypoxia-tolerant fish species/strains. This review summarizes the process of the hypoxia signaling pathway and its regulation, as well as the mechanism of hypoxia adaptation in fishes.

  12. Hypoxia in the Northern Gulf of Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Dale, Virginia H [ORNL

    2010-01-01

    Since 1985, scientists have been documenting a hypoxic zone in the Gulf of Mexico each year. The hypoxic zone, an area of low dissolved oxygen that cannot support marine life, generally manifests itself in the spring. Since marine species either die or flee the hypoxic zone, the spread of hypoxia reduces the available habitat for marine species, which are important for the ecosystem as well as commercial and recreational fishing in the Gulf. Since 2001, the hypoxic zone has averaged 16,500 km{sup 2} during its peak summer months, an area slightly larger than the state of Connecticut, and ranged from a low of 8,500 km{sup 2} to a high of 22,000 km{sup 2}. To address the hypoxia problem, the Mississippi River/Gulf of Mexico Watershed Nutrient Task Force (or Task Force) was formed to bring together representatives from federal agencies, states, and tribes to consider options for responding to hypoxia. The Task Force asked the White House Office of Science and Technology Policy to conduct a scientific assessment of the causes and consequences of Gulf hypoxia through its Committee on Environment and Natural Resources (CENR). In 2000 the CENR completed An Integrated Assessment: Hypoxia in the Northern Gulf of Mexico (or Integrated Assessment), which formed the scientific basis for the Task Force's Action Plan for Reducing, Mitigating, and Controlling Hypoxia in the Northern Gulf of Mexico (Action Plan, 2001). In its Action Plan, the Task Force pledged to implement ten management actions and to assess progress every 5 years. This reassessment would address the nutrient load reductions achieved, the responses of the hypoxic zone and associated water quality and habitat conditions, and economic and social effects. The Task Force began its reassessment in 2005. In 2006 as part of the reassessment, USEPA's Office of Water, on behalf of the Task Force, requested that the U.S. Environmental Protection Agency (USEPA) Science Advisory Board (SAB) convene an independent

  13. Myeloid cell-derived HIF attenuates inflammation in UUO-induced kidney injury

    Science.gov (United States)

    Kobayashi, Hanako; Gilbert, Victoria; Liu, Qingdu; Kapitsinou, Pinelopi P.; Unger, Travis L.; Rha, Jennifer; Rivella, Stefano; Schlöndorff, Detlef; Haase, Volker H.

    2012-01-01

    Renal fibrosis and inflammation are associated with hypoxia, and tissue pO2 plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type-specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, while activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with down-regulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in non-injured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury. PMID:22490864

  14. 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.

  15. Mechanisms of cell protection by adaptation to chronic and acute hypoxia: molecular biology and clinical practice.

    Science.gov (United States)

    Corbucci, G G; Marchi, A; Lettieri, B; Luongo, C

    2005-11-01

    Several experimental and clinical studies have shown that specific biochemical and molecular pathways are involved in the myocardial and skeletal muscle cell tolerance to acute and/or chronic hypoxic injury. A number of different factors were proposed to play a role in the preservation of tissue viability, but to a few of them a pivotal role in the adaptive mechanisms to hypoxic stimuli could be ascribed. Starting from the observation that mitochondrial electron transport chain (ETC) enzymic complexes are the targets of oxygen reduced availability, most of data are compatible with a mechanism of enzymic adaptation in which the nitric oxide (NO) generation plays the major role. If the partial and reversible NO-induced inhibition of ETC enzymic complexes represents the most rapid and prominent adaptive mechanism in counteracting the damaging effects of hypoxia, the sarcolemmal and mitochondrial K+(ATP) channels activation results to be closely involved in cytoprotection. This process is depending on protein kinase C (PKC) isoform activation triggered by reactive oxygen species (ROS) generation, adenosine triphosphate (ATP) depletion and Ca++ overload. It is well known that all these factors are present in hypoxia-induced oxidative damage and mitochondrial Ca++ altered pools represent powerful stimuli in the damaging processes. The activation of mitochondrial K+(ATP) channels leads to a significant reduction of Ca++ influx and attenuation of mitochondrial Ca++ overload. Closely linked to these adaptive changes signal transduction pathways are involved in the nuclear DNA damage and repair mechanisms. On this context, an essential role is played by the hypoxia-induced factor-1alpha (HIF-1alpha) in terms of key transcription factor involved in oxygen-dependent gene regulation. The knowledge of the biochemical and molecular sequences involved in these adaptive processes call for a re-evaluation of the therapeutic approach to hypoxia-induced pathologies. On this light

  16. Effects of hypoxia and glucose-removal condition on muscle contraction of the smooth muscles of porcine urinary bladder.

    Science.gov (United States)

    Nagai, Yuta; Kaneda, Takeharu; Miyamoto, Yasuyuki; Nuruki, Takaomi; Kanda, Hidenori; Urakawa, Norimoto; Shimizu, Kazumasa

    2016-01-01

    To elucidate the dependence of aerobic energy metabolism and utilization of glucose in contraction of urinary bladder smooth muscle, we investigated the changes in the reduced pyridine nucleotide (PNred) fluorescence, representing glycolysis activity, and determined the phosphocreatine (PCr) and ATP contents of the porcine urinary bladder during contractions induced by high K(+) or carbachol (CCh) and with and without hypoxia (achieved by bubbling N2 instead of O2) or in a glucose-free condition. Hyperosmotic addition of 65 mM KCl (H-65K(+)) and 1 µM CCh induced a phasic contraction followed by a tonic contraction. A glucose-free physiological salt solution (PSS) did not change the subsequent contractile responses to H-65K(+) and CCh. However, hypoxia significantly attenuated H-65K(+)- and CCh-induced contraction. H-65K(+) and CCh induced a sustained increase in PNred fluorescence, representing glycolysis activity. Hypoxia enhanced H-65K(+)- and CCh-induced increases in PNred fluorescence, whereas glucose-free PSS decreased these increases, significantly. In the presence of H-65K(+), hypoxia decreased the PCr and ATP contents; however, the glucose-free PSS did not change the PCr contents. In conclusion, we demonstrated that high K(+)- and CCh-induced contractions depend on aerobic metabolism and that an endogenous substrate may be utilized to maintain muscle contraction in a glucose-free PSS in the porcine urinary bladder.

  17. A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis

    Institute of Scientific and Technical Information of China (English)

    Xiqing Chai; Weina Kong; Lingyun Liu; Wenguo Yu; Zhenqing Zhang; Yimin Sun

    2014-01-01

    Hypoxia-inducible factor 1 (HIF-1) attenuates amyloid-beta protein neurotoxicity and decreases apoptosis induced by oxidative stress or hypoxia in cortical neurons. In this study, we construct-ed a recombinant adeno-associated virus (rAAV) vector expressing the human HIF-1αgene (rAAV-HIF-1α), and tested the assumption that rAAV-HIF-1αrepresses hippocampal neuronal apoptosis induced by amyloid-beta protein. Our results conifrmed that rAAV-HIF-1αsigniifcant-ly reduces apoptosis induced by amyloid-beta protein in primary cultured hippocampal neurons. Direct intracerebral rAAV-HIF-1αadministration also induced robust and prolonged HIF-1αproduction in rat hippocampus. Single rAAV-HIF-1αadministration resulted in decreased apoptosis of hippocampal neurons in an Alzheimer’s disease rat model established by intrace-rebroventricular injection of aggregated amyloid-beta protein (25-35). Our in vitro and in vivo ifndings demonstrate that HIF-1 has potential for attenuating hippocampal neuronal apoptosis induced by amyloid-beta protein, and provides experimental support for treatment of neurode-generative diseases using gene therapy.

  18. HIF-1α Promotes A Hypoxia-Independent Cell Migration.

    Science.gov (United States)

    Li, Liyuan; Madu, Chikezie O; Lu, Andrew; Lu, Yi

    2010-01-01

    Hypoxia-inducible factor-1α (HIF-1α) is known as a transactivator for VEGF gene promoter. It can be induced by hypoxia. However, no study has been done so far to dissect HIF-1α-mediated effects from hypoxia or VEGF-mediated effects. By using a HIF-1α knockout (HIF-1α KO) cell system in mouse embryonic fibroblast (MEF) cells, this study analyzes cell migration and HIF-1α, hypoxia and VEGF activation. A hypoxia-mediated HIF-1α induction and VEGF transactivation were observed: both HIF-1α WT lines had significantly increased VEGF transactivation, as an indicator for HIF-1α induction, in hypoxia compared to normoxia; in contrast, HIF-1α KO line had no increased VEGF transactivation under hypoxia. HIF-1α promotes cell migration: HIF-1α-KO cells had a significantly reduced migration compared to that of the HIF-1α WT cells under both normoxia and hypoxia. The significantly reduced cell migration in HIF-1α KO cells can be partially rescued by the restoration of WT HIF-1α expression mediated by adenoviral-mediated gene transfer. Interestingly, hypoxia has no effect on cell migration: the cells had a similar cell migration rate under hypoxic and normoxic conditions for both HIF-1α WT and HIF-1α KO lines, respectively. Collectively, these data suggest that HIF-1α plays a role in MEF cell migration that is independent from hypoxia-mediated effects.

  19. Planetary Ices Attenuation Properties

    Science.gov (United States)

    McCarthy, Christine; Castillo-Rogez, Julie C.

    In this chapter, we review the topic of energy dissipation in the context of icy satellites experiencing tidal forcing. We describe the physics of mechanical dissipation, also known as attenuation, in polycrystalline ice and discuss the history of laboratory methods used to measure and understand it. Because many factors - such as microstructure, composition and defect state - can influence rheological behavior, we review what is known about the mechanisms responsible for attenuation in ice and what can be inferred from the properties of rocks, metals and ceramics. Since attenuation measured in the laboratory must be carefully scaled to geologic time and to planetary conditions in order to provide realistic extrapolation, we discuss various mechanical models that have been used, with varying degrees of success, to describe attenuation as a function of forcing frequency and temperature. We review the literature in which these models have been used to describe dissipation in the moons of Jupiter and Saturn. Finally, we address gaps in our present knowledge of planetary ice attenuation and provide suggestions for future inquiry.

  20. Cordyceps sinensis Increases Hypoxia Tolerance by Inducing Heme Oxygenase-1 and Metallothionein via Nrf2 Activation in Human Lung Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Mrinalini Singh

    2013-01-01

    Full Text Available Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy of Cordyceps sinensis in facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract of Cordyceps sinensis appreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1, MT (metallothionein and Nrf2 (nuclear factor erythroid-derived 2-like 2. In contrast, lower level of NFκB (nuclear factor kappaB and tumor necrosis factor-α observed which might be due to higher levels of HO1, MT and transforming growth factor-β. Further, increase in HIF1 (hypoxia inducible factor-1 and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly, Cordyceps sinensis treatment under normoxia did not regulate the expression HIF1, NFκB and their regulated genes evidencing that Cordyceps sinensis per se did not have an effect on these transcription factors. Overall, Cordyceps sinensis treatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NFκB levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia.

  1. Cordyceps sinensis Increases Hypoxia Tolerance by Inducing Heme Oxygenase-1 and Metallothionein via Nrf2 Activation in Human Lung Epithelial Cells

    Science.gov (United States)

    Manickam, Manimaran; Misra, Kshipra

    2013-01-01

    Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy of Cordyceps sinensis in facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract of Cordyceps sinensis appreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1), MT (metallothionein) and Nrf2 (nuclear factor erythroid-derived 2-like 2). In contrast, lower level of NFκB (nuclear factor kappaB) and tumor necrosis factor-α observed which might be due to higher levels of HO1, MT and transforming growth factor-β. Further, increase in HIF1 (hypoxia inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly, Cordyceps sinensis treatment under normoxia did not regulate the expression HIF1, NFκB and their regulated genes evidencing that Cordyceps sinensis per se did not have an effect on these transcription factors. Overall, Cordyceps sinensis treatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NFκB levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia. PMID:24063008

  2. Effects of Hypobaric Cold Storage Technology on Preservation of Fresh-cut Fruits and Vegetables%减压冷藏技术对鲜切果蔬保鲜效果的研究

    Institute of Scientific and Technical Information of China (English)

    胡欣; 张长峰; 郑先章

    2012-01-01

    以花王菜等6种蔬菜和苹果为试材,研究减压冷藏技术对鲜切果蔬的保鲜效果.结果表明,减压冷藏处理技术是可应用于鲜切果蔬保鲜的新技术.将果蔬原材料经减压冷藏处理(压力范围为600~3 200 Pa),再清洗切割加工成鲜切产品,可比普通冷藏有效减缓山药、土豆和苹果等鲜切产品的褐变;明显减少鲜切花王菜、鸡毛菜和空心菜的萎蔫、黄叶与腐烂,保持鲜切绿叶菜的新鲜品质;切割前的减压冷藏结合真空预冷,可大大减轻鲜切西兰花的黄化、萎蔫、花粒变大、脱落及切面的褐变与腐烂,显著延长鲜切果蔬的冷藏货架期及冷链断链保鲜期.%The experiments used 6 kinds of vegetables and apple as material to research the preservation effects by using hypobaric cold storage technology. The results indicated that, the hypobaric cold storage treatment technology was an advanced new technology of preservation and process for fresh-cut vegetables and fruits. The raw materials of fruits and vegetables were treated by hypobaric cold storage, pressure 600-3 200 Pa, followed washing and cutting to fresh-cut products. Compared with normal cold storage, the hypobaric cold storage treatment technology could retard the brown degree of cut face of yam, potato and apple, decrease the wilting, yellow leaf and rotting of Huawang vegetable, Jimao vegetable and swamp cabbage, also kept their good fresh quality. Hypobaric cold storage before cutting combined with vaccum pre -cooling treatment could greatly readuce the yellow changed, wilting, flower grain growing and dropping, brown degree of cut face and rotting of broccoli, and prolong the shelf life of fresh-cut fruits and vegetables and preservation period of cold chain scission.

  3. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    Science.gov (United States)

    Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

  4. Acute normobaric hypoxia stimulates erythropoietin release.

    Science.gov (United States)

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

    2008-01-01

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

  5. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Michal Amit Rahat

    2011-09-01

    Full Text Available Monocytes and Macrophages (Mo/Mϕ exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mϕ, combating invading pathogens and tumor cells (classically activated or M1 Mo/Mϕ, orchestrating wound healing (alternatively activated or M2 Mo/Mϕ, and restoring homeostasis after an inflammatory response (resolution Mϕ. Hypoxia is an important factor in the Mϕ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mϕ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mϕ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators HIF-1 and NF-κB, as well as other transcription factors (e.g. AP-1, Erg-1, but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mϕ pro-angiogenic mediators, suppress M1 Mϕ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mϕ into an activation state which approximate the alternatively activated or resolution Mϕ.

  6. 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 

  7. Dietary supplementation of some antioxidants against hypoxia

    Institute of Scientific and Technical Information of China (English)

    Sanaa Ahmed Ali; Hanan Farouk Aly; Lilla Mohammed Faddah; Zeenat F Zaidi

    2012-01-01

    The present study aims to clarifythe protective effect of supplementation with some antioxidants,such as idebenone (200 mg/kg,ip),melatonin (10 mg/kg,ip) and arginine (200 mg/kg,ip) and their combination,on liver function (T.protein,albumin,alanine aminotransferase,aspartate aminotransferase and alkaline phosphatase),energetic parameters (adenosine triphosphate,adenosine diphosphate,adenosine monophosphate,inorganic phosphate,total adenylate,adenylate energy charge and potential phosphate).The effect on glycolytic and glycogenolytic enzymes (glucose,glycogen,glycogen phosphorylase,pyruvate kinase and phosphofructokinase against hypoxia) was also studied.The drugs were administered 24 and 1 h prior sodium nitrite intoxication.All biochemical parameters were estimated 1 h after sodium nitrite injection.Injection of sodium nitrite (75 mg/kg,sc) produced a significant disturbance in all biochemical parameters of liver function,energetic parameters and glycolytic and glycogenolytic enzymes.Hepatic damage was confirmed by histopathological examination of the liver as compared to controls.The marked changes in hepatic cells induced by sodium nitrite were completely abolished by pretreatment with the drug combination,suggesting potential protection against sodium nitrite-induced hypoxia.It could be concluded that a combination of both idebenone and melatonin or idebenone and arginine provides potential protection against sodium nitrite-induced hypoxia by improving biochemical parameters and preserving liver histology.

  8. Structural integration in hypoxia-inducible factors

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Dalei; Potluri, Nalini; Lu, Jingping; Kim, Youngchang; Rastinejad, Fraydoon

    2015-08-20

    The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

  9. Hemodynamic and ventilatory response to different levels of hypoxia and hypercapnia in carotid body-denervated rats

    Directory of Open Access Journals (Sweden)

    João Paulo J. Sabino

    2013-01-01

    Full Text Available OBJECTIVE: Chemoreceptors play an important role in the autonomic modulation of circulatory and ventilatory responses to changes in arterial O2 and/or CO2. However, studies evaluating hemodynamic responses to hypoxia and hypercapnia in rats have shown inconsistent results. Our aim was to evaluate hemodynamic and respiratory responses to different levels of hypoxia and hypercapnia in conscious intact or carotid body-denervated rats. METHODS: Male Wistar rats were submitted to bilateral ligature of carotid body arteries (or sham-operation and received catheters into the left femoral artery and vein. After two days, each animal was placed into a plethysmographic chamber and, after baseline measurements of respiratory parameters and arterial pressure, each animal was subjected to three levels of hypoxia (15, 10 and 6% O2 and hypercapnia (10% CO2. RESULTS: The results indicated that 15% O2 decreased the mean arterial pressure and increased the heart rate (HR in both intact (n = 8 and carotid body-denervated (n = 7 rats. In contrast, 10% O2did not change the mean arterial pressure but still increased the HR in intact rats, and it decreased the mean arterial pressure and increased the heart rate in carotid body-denervated rats. Furthermore, 6% O2 increased the mean arterial pressure and decreased the HR in intact rats, but it decreased the mean arterial pressure and did not change the HR in carotid body-denervated rats. The 3 levels of hypoxia increased pulmonary ventilation in both groups, with attenuated responses in carotid body-denervated rats. Hypercapnia with 10% CO2 increased the mean arterial pressure and decreased HR similarly in both groups. Hypercapnia also increased pulmonary ventilation in both groups to the same extent. CONCLUSION: This study demonstrates that the hemodynamic and ventilatory responses varied according to the level of hypoxia. Nevertheless, the hemodynamic and ventilatory responses to hypercapnia did not depend on the

  10. Frequency Dependent Attenuation Revisited

    CERN Document Server

    Richard, Kowar; Xavier, Bonnefond

    2009-01-01

    The work is inspired by thermo-and photoacoustic imaging, where recent efforts are devoted to take into account attenuation and varying wave speed parameters. In this paper we study causal equations describing propagation of attenuated pressure waves. We review standard models like frequency power laws and and the thermo-viscous equation. The lack of causality of standard models in the parameter range relevant for photoacoustic imaging requires to derive novel equations. The main ingredients for deriving causal equations are the Kramers-Kronig relation and the mathematical concept of linear system theory. The theoretical results of this work are underpined by numerical experiments.

  11. 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......, as reflected by the higher alveolar-arterial O2 difference in hypoxia (P VO2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% (P ... blood flow was also lower (by 22%, P VO2 max (r = 0.98, P VO2 max in severe acute hypoxia...

  12. The effect of hypobaric pressure exposure on electrogastrogram of pilots%低气压暴露对飞行员胃电图的影响

    Institute of Scientific and Technical Information of China (English)

    徐先荣; 翟丽红; 徐华; 刘玉华

    2013-01-01

    目的:观察低气压暴露对飞行员胃电图(electrogastrogram,EGG)的影响。方法25名参加改装体检的直升机飞行员坐于低压舱内,记录EGG 4 min,然后以20 m/s速度上升,分别在1000、2000、3000、4000 m处各停留10 min,并记录EGG 4 min,再以5 m/s速度下降返回地面,观察不同高度EGG的平均幅值、平均频率、平均节律紊乱百分比和正常慢波百分比等指标变化。结果低气压暴露对飞行员EGG的影响包括:①平均幅值总体呈现下降趋势,其中1000 m和3000 m高度EGG平均幅值为304.2•V和297.6•V,与地面EGG平均幅值357.7•V相比差异有统计学意义(t=2.69,2.42,P<0.05),但2例有轻度腹胀者表现为相反的平均幅值上升;②平均频率总体无明显变化,但2例有轻度腹胀者平均频率稍快;③平均节律紊乱百分比仅3000 m高度(24.3%)明显降低,与地面(28.2%)相比差异有统计学意义(t=3.23,P<0.01),但2例有轻度腹胀者反而增加;④正常慢波百分比总体呈现为无明显改变。结论4000 m不同高度低气压暴露对飞行员EGG的影响差异较大,但对明显腹胀和腹痛者,EGG的平均幅值和平均节律紊乱百分比可能提供有价值的客观依据。如果在影响因素的控制方面做更深入细致的工作,有望将EGG作为高空胃肠胀气的客观评价指标。%Objective We aimed to study the effect of hypobaric pressure exposure on the electrogastrogram (EGG) of pilots. Methods A total of 25 helicopter pilots under physical examination for change to new-type of aircraft participated in this study.The examinees were seated in a hypobaric chamber and recorded with EGG for 4 minutes. They then ascended at a speed of 20 m/s,stayed at 1000,2000,3000,4000 m for 10 minutes respectively,and were recorded with EGG for 4 minutes at each stop. The pilots finally descended back to the ground at a speed of 5 m/s. Indices such as the

  13. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers.

    NARCIS (Netherlands)

    Goethals, L.; Debucquoy, A.; Perneel, C.; Geboes, K.; Ectors, N.; Schutter, H. De; Penninckx, F.; McBride, W.H.; Begg, A.C.; Haustermans, K.

    2006-01-01

    PURPOSE: To detect and quantify hypoxia in colorectal adenocarcinomas by use of pimonidazole and iododeoxyuridine (IdUrd) as extrinsic markers and carbonic anhydrase IX (CA IX), microvessel density (MVD), epidermal growth-factor receptor (EGFR), and vascular endothelial growth factor (VEGF) as intri

  14. 低压低氧预处理对加速度暴露大鼠心肌损伤的保护作用%Protection of hypobaric hypoxia preconditioning on myocardial injuries of rats after acceleration exposured

    Institute of Scientific and Technical Information of China (English)

    叶博; 张国荣; 黄俊梅; 尹哲; 陶磊

    2014-01-01

    目的:从心肌抗氧化系统及一氧化氮(NO)代谢通路研究低压低氧预处理对加速度环境下心肌细胞病理生理变化的影响,解释航空加速度环境下心肌组织的损伤机制,探讨低压低氧预处理的保护机制.方法24只雄性SD大鼠随机分为3组(n=8),C组为空白对照组,HHP+10 Gz组为5000 m高空低压低氧预处理4 h/d连续4 d后暴露10 Gz加速度组,10 Gz组为直接暴露10 Gz加速度组,各组按上述处理后,取大鼠心肌组织,委托北京华英生物技术研究室检测超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-PX)、谷胱甘肽(GSH)、丙二醛(MDA)、热休克蛋白-70(HSP-70)以及一氧化氮(NO)、亚硝酸盐(NO2-)、硝酸盐(NO3-)、内皮型一氧化氮合酶(eNOS)、诱导型一氧化氮合酶(iNOS)、神经型一氧化氮合酶(nNOS)的变化.结果 SOD水平院C组[(8.242±1.562)U/mg]和HHP+10 Gz组[(7.660±1.208)U/mg]高于10 Gz组[(4.773±0.665)U/mg],差异均有统计学意义(均P0.054);HSP-70水平院C组[(1.415±0.500)ng/mg]低于HHP+10 Gz组[(2.189±0.659)ng/mg]和10 Gz组[(2.452±0.926)ng/mg],差异均有统计学意义(均P0.05). HSP-70 levls: group C [(1.415±0.500) ng/mg] was lower than group HHP+10 Gz [(2.189±0.659) ng/mg] and group 10 Gz [(2.452±0.926) ng/mg], the differences were statistically significant (P<0.05). NO level: group C [(1.932±0.496) μmol/g] was lower than group HHP+10 Gz [(2.751±0.784) μmol/g] and group 10 Gz [(3.185±0.769)μmol/g], the differences were statistically significant (P< 0.05). NO2-level: group C [(1.277±0.279) μmol/g] was lower than group HHP+10 Gz [(1.800±0.568) μmol/g] and group 10 Gz [(1.970±0.362) μmol/g], the differences were statistically significant (P < 0.05). NO3- level: group C [(2.191±0.426) μmol/g] was lower than group HHP+10 Gz [(2.898±0.500) μmol/g] and group 10 Gz [(2.995±0.445) μmol/g], the differences were statistically significant (P <0.05). eNOS level:group C [(3.726±0.498) U/mg] was lower than group HHP+10 Gz [(5.081±0.994) U/mg] and group 10 Gz [(5.937±1.423) U/mg], the differences were statistically significant (P<0.05). iNOS level: group C [(3.668±0.379) U/mg] was lower than group HHP+10 Gz [(4.382±0.567) U/mg] and group 10 Gz [(4.986±1.318) U/mg], the differences were statistically significant (P<0.05). nNOS level:group C [(0.830±0.117) U/mg] was lower than group HHP+10 Gz [(1.044±0.190) U/mg] and group 10 Gz [(1.226±0.300) U/mg], the differences were statistically significant (P< 0.05). Conclusion HHP can reduce oxidative damage of myocardial tissue caused by acceleration and has myocardial protective effect, the mechanism is related to enhancing the activity of antioxidant enzymes and reducing oxidative stress on the activation of NOS and then inhibiting the release of NO in rats.

  15. Lysyl oxidase is essential for hypoxia-induced metastasis

    DEFF Research Database (Denmark)

    Erler, Janine Terra; Bennewith, Kevin L; Nicolau, Monica

    2006-01-01

    role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor...

  16. 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.

  17. Hypoxia-regulated MicroRNAs in gastroesophageal cancer

    DEFF Research Database (Denmark)

    Winther, M.; Alsner, J.; Sørensen, B.S.

    2016-01-01

    Background/aim: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). Materials and Methods: microRNA expression changes induced by hypoxia in human GEC cell lines were...

  18. Hypoxia-induced retinopathy model in adult zebrafish

    DEFF Research Database (Denmark)

    Cao, Ziquan; Jensen, Lasse D.; Rouhi, Pegah;

    2010-01-01

    . In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia...

  19. Hypoxia as a Biomarker and for Personalized Radiation Oncology

    DEFF Research Database (Denmark)

    Vordermark, Dirk; Horsman, Michael R

    2016-01-01

    , cervix cancer and sarcoma. Exogenous markers have been used for immunohistochemical detection of hypoxic tumor areas (pimonidazole) or for positron-emission tomography (PET) imaging (misonidazole). Overexpression of hypoxia-related proteins such as hypoxia-inducible factor-1α (HIF-1α) has also been...

  20. Behavioral, Ventilatory and Thermoregulatory Responses to Hypercapnia and Hypoxia in the Wistar Audiogenic Rat (WAR Strain.

    Directory of Open Access Journals (Sweden)

    Érica Maria Granjeiro

    Full Text Available We investigated the behavioral, respiratory, and thermoregulatory responses elicited by acute exposure to both hypercapnic and hypoxic environments in Wistar audiogenic rats (WARs. The WAR strain represents a genetic animal model of epilepsy.Behavioral analyses were performed using neuroethological methods, and flowcharts were constructed to illustrate behavioral findings. The body plethysmography method was used to obtain pulmonary ventilation (VE measurements, and body temperature (Tb measurements were taken via temperature sensors implanted in the abdominal cavities of the animals.No significant difference was observed between the WAR and Wistar control group with respect to the thermoregulatory response elicited by exposure to both acute hypercapnia and acute hypoxia (p>0.05. However, we found that the VE of WARs was attenuated relative to that of Wistar control animals during exposure to both hypercapnic (WAR: 133 ± 11% vs. Wistar: 243 ± 23%, p<0.01 and hypoxic conditions (WAR: 138 ± 8% vs. Wistar: 177 ± 8%; p<0.01. In addition, we noted that this ventilatory attenuation was followed by alterations in the behavioral responses of these animals.Our results indicate that WARs, a genetic model of epilepsy, have important alterations in their ability to compensate for changes in levels of various arterial blood gasses. WARs present an attenuated ventilatory response to an increased PaCO2 or decreased PaO2, coupled to behavioral changes, which make them a suitable model to further study respiratory risks associated to epilepsy.

  1. Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yanlong [School of Pharmacy, Wenzhou Medical College, Wenzhou (China); Department of Medicine, University of Louisville, Louisville, KY (United States); Wang, Chunhong [Second Hospital, Jilin University, Changchun (China); Department of Medicine, University of Louisville, Louisville, KY (United States); Wang, Yuhua [College of Food Science and Engineering, Jilin Agricultural University, Changchun (China); Department of Medicine, University of Louisville, Louisville, KY (United States); Ma, Zhenhua [First Hospital, Xi' an Jiaotong University, Xi' an (China); Department of Medicine, University of Louisville, Louisville, KY (United States); Xiao, Jian [School of Pharmacy, Wenzhou Medical College, Wenzhou (China); McClain, Craig [Department of Medicine, University of Louisville, Louisville, KY (United States); Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY (United States); Alcohol Research Center, University of Louisville, Louisville, KY (United States); Robley Rex Veterans Affairs Medical Center, Louisville, KY (United States); Li, Xiaokun [School of Pharmacy, Wenzhou Medical College, Wenzhou (China); Feng, Wenke, E-mail: wenke.feng@louisville.edu [School of Pharmacy, Wenzhou Medical College, Wenzhou (China); Department of Medicine, University of Louisville, Louisville, KY (United States); Alcohol Research Center, University of Louisville, Louisville, KY (United States)

    2012-10-15

    Fibroblast growth factor-21 (FGF21) is a potential metabolic regulator with multiple beneficial effects on metabolic diseases. FGF21 is mainly expressed in the liver, but is also found in other tissues including the intestine, which expresses β-klotho abundantly. The intestine is a unique organ that operates in a physiologically hypoxic environment, and is responsible for the fat absorption processes including triglyceride breakdown, re-synthesis and absorption into the portal circulation. In the present study, we investigated the effects of hypoxia and the chemical hypoxia inducer, cobalt chloride (CoCl{sub 2}), on FGF21 expression in Caco-2 cells and the consequence of fat accumulation. Physical hypoxia (1% oxygen) and CoCl{sub 2} treatment decreased both FGF21 mRNA and secreted protein levels. Gene silence and inhibition of hypoxia-inducible factor-α (HIFα) did not affect the reduction of FGF21 mRNA and protein levels by hypoxia. However, CoCl{sub 2} administration caused a significant increase in oxidative stress. The addition of n-acetylcysteine (NAC) suppressed CoCl{sub 2}-induced reactive oxygen species (ROS) formation and completely negated CoCl{sub 2}-induced FGF21 loss. mRNA stability analysis demonstrated that the CoCl{sub 2} administration caused a remarkable reduction in FGF21 mRNA stability. Furthermore, CoCl{sub 2} increased intracellular triglyceride (TG) accumulation, along with a reduction in mRNA levels of lipid lipase, hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), and an increase of sterol regulatory element-binding protein-1c (SREBP1c) and stearoyl-coenzyme A (SCD1). Addition of both NAC and recombinant FGF21 significantly attenuated the CoCl{sub 2}-induced TG accumulation. In conclusion, the decrease of FGF21 in Caco-2 cells by chemical hypoxia is independent of HIFα, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and

  2. Overexpression of ERβ is sufficient to inhibit hypoxia-inducible factor-1 transactivation

    Energy Technology Data Exchange (ETDEWEB)

    Park, Choa; Lee, YoungJoo, E-mail: yjlee@sejong.ac.kr

    2014-07-18

    Highlights: • We examined the effect of ERβ specific ligand on HIF-1 inhibition. • DPN down-regulates the ARNT protein levels in PC3 cells. • DPN did not show additional effect in ERβ transfected MCF-7 cells. • Our study shows that unliganded ERβ is sufficient to inhibit HIF-1 in systems of overexpression. - Abstract: Estrogen receptor (ER) β is predicted to play an important role in the prevention of breast cancer development and progression. We have previously shown that ERβ suppresses hypoxia inducible factor (HIF)-1-mediated transcription through aryl hydrocarbon receptor nuclear translocator (ARNT) degradation via ubiquitination processes. In this study, we attempted to examine the effect of ERβ specific ligand on HIF-1 inhibition in ERβ positive PC3 cells and ERβ transfected MCF-7 cells. ERβ specific agonist diarylpropionitrile (DPN) stimulated estrogen response element (ERE)-luciferase activity in a similar fashion to estradiol in PC3 cells. We observed that DPN down-regulates the ARNT protein levels leading to an attenuation of hypoxia-induced hypoxia response element (HRE)-driven luciferase reporter gene activation in PC3 cells. Treatment of DPN reduced vascular endothelial growth factor (VEGF) expression and co-treatment with ERβ specific antagonist PHTPP abrogated the effect in PC3 cells. We then examined the effect of DPN in ERβ transfected MCF-7 cells. HIF-1 transcriptional activity repression by ERβ was not further reduced by DPN, as examined by HRE-driven luciferase assays. Expression of ERβ significantly decreased VEGF secretion and ARNT expression under hypoxic conditions. However, DPN did not additionally affect this suppression in MCF-7 cells transfected with ERβ. This result shows that unliganded ERβ is sufficient to inhibit HIF-1 in systems of overexpression.

  3. 减压贮藏对番茄果实抗氧化物质和抗氧化酶的影响%Effect of hypobaric storage on antioxidant contents and antioxidant enzymes in tomato fruit

    Institute of Scientific and Technical Information of China (English)

    郭润姿; 白阳; 郭文岚; 寇晓虹

    2013-01-01

    为了研究不同减压处理对番茄果实后熟过程中抗氧化性的影响,以粉冠番茄为材料,研究了在43.6、73.0kPa和常压三个压力条件下,番茄中维生素C、番茄红素和谷胱甘肽含量,以及超氧化物歧化酶(SOD)、过氧化物酶(POD)和过氧化氢酶(CAT)的活性变化规律.结果表明,减压贮藏显著推迟了番茄中维生素C含量的高峰,在一定程度上延迟了番茄红素和谷胱甘肽含量的高峰,并且压力越低效果越显著(p<0.05);在果实后熟过程中SOD、CAT活性逐渐下降,而减压处理可显著抑制SOD活性下降(p<0.05).POD活性在贮藏期间呈现先降后升的趋势,减压处理可以有效地保持较高的抗氧化酶活性.结论:减压处理贮藏可以显著保护番茄果实中的抗氧化物质和抗氧化酶活性,而且一定范围内压力越低效果越好.%In order to study effects of different hypobaric conditions(43.6,73.0,101.3kPa) on antioxidant capacity of tomato,the experiment mainly determined that the contents of vitamin C,lycopene,glutathione and the activity changes of superoxide dismutase(SOD),peroxidase(POD),catalase(CAT). The result showed that hypobaric storage significantly delayed the vitamin C peak of tomato fruit(p<0.05) and the peaks of lycopene and glutathione to some extent were delayed,the lower the pressure,the later of the peak appears. SOD and CAT activities in tomato declined during the storage period after-ripening,hypobaric conditions significantly inhibited the decline of SOD activity(p<0.05). The activity of POD firstly decreased and then increased during storage,hypobaric conditions could effectively maintain higher activities of antioxidant enzyme. In summary,the tomato storage quality and antioxidant activity in hypobaric conditions were better than in atmospheric pressure,and at a certain rang,the lower pressure,the better effect of the hypobaric storage.

  4. The effect of hypoxia on PGE2-stimulated cAMP generation in HMEC-1.

    Science.gov (United States)

    Wiktorowska-Owczarek, Anna; Owczarek, Jacek

    2015-06-01

    Prostaglandin E2 (PGE2) is generated in various cells, including endothelial cells, and is responsible for various functions, such as vascular relaxation and angiogenesis. Effects of PGE2 are mediated via receptors EP1-EP4, among which EP2 and EP4 are coupled to Gs protein which activates adenylate cyclase (AC) and cAMP synthesis. The aim of this work was to study the ability of human microvascular endothelial cells (HMEC-1) to synthesize cAMP in the presence of PGE2, and to determine the effect of hypoxia on the PGE2- stimulated cAMP level. It was decided to evaluate the effect of PGE2 on the secretion of VEGF, an inducer of angiogenesis. In summary, our findings show that PGE2 induces cAMP production, but hypoxia may impair PGE2-stimulated activity of the AC-cAMP signaling pathway. These results suggest that the cardioprotective effect of PGE2/EP4/cAMP may be attenuated during ischemia. Furthermore, this study indicates that the pro-angiogenic effect of PGE2 is not associated with VEGF secretion in HMEC-1 cells.

  5. 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......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...... 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...

  6. Boron PLA for oxygen sensing & hypoxia imaging

    Directory of Open Access Journals (Sweden)

    Cassandra L. Fraser

    2009-10-01

    Full Text Available Oxygen is essential for many forms of life and its depletion in the body and the environment can lead to deleterious effects. Low oxygen conditions, even anoxia, are associated with eutrophication of lakes and rivers, wherein an over abundance of nutrients often caused by pollution result in excessive plant growth and decay, threatening water quality, ecosystem balance, and aquatic life. In the body, low oxygen conditions or hypoxia may be generalized, as can occur at high altitude or during strenuous exercise, or localized in particular tissues, when there is a mismatch between oxygen supply and demand. Hypoxia is present in many important diseases as well. Low oxygen levels in tumors are often associated with biochemical changes, increased invasiveness, cancer progression, and resistance to radiation and chemotherapies. Vascular blockage in strokes, heart attacks, and peripheral artery disease, which is common in diabetes, are other situations where oxygen levels can drop precipitously and cause great damage to affected tissues. Clearly, innovative sensing technologies that provide new insight into these many oxygen dependent processes can impact global society in significant ways.

  7. Ultrasonic attenuation in pearlitic steel.

    Science.gov (United States)

    Du, Hualong; Turner, Joseph A

    2014-03-01

    Expressions for the attenuation coefficients of longitudinal and transverse ultrasonic waves are developed for steel with pearlitic microstructure. This type of lamellar duplex microstructure influences attenuation because of the lamellar spacing. In addition, longitudinal attenuation measurements were conducted using an unfocused transducer with 10 MHz central frequency on the cross section of a quenched railroad wheel sample. The dependence of longitudinal attenuation on the pearlite microstructure is observed from the changes of longitudinal attenuation from the quenched tread surface to deeper locations. The results show that the attenuation value is lowest and relatively constant within the quench depth, then increases linearly. The experimental results demonstrate a reasonable agreement with results from the theoretical model. Ultrasonic attenuation provides an important non-destructive method to evaluate duplex microstructure within grains which can be implemented for quality control in conjunction with other manufacturing processes.

  8. Occurrence of hypoxia in the wards of a teaching hospital

    Directory of Open Access Journals (Sweden)

    Virendra Singh

    2012-01-01

    Full Text Available Objective : Appearance of hypoxia in a patient may be an indicator of a serious medical condition that can have grave consequences. Clinical evaluation fails to detect majority of the patients of hypoxia, and therefore, it may remain unnoticed in the wards. We planned to assess the magnitude of hypoxia in different wards of our tertiary care hospital. Materials and Methods: We studied all the patients admitted in various medical and surgical wards during 1 week of study. Oxygen saturation (SpO 2 was measured with the help of a pulse oximeter in all the patients who remained admitted for at least 24 h. Hypoxia was diagnosed in a patient when he had SpO 2 less than 90%. Results: During the study period, 1167 patients were admitted in various wards of the hospital. Hypoxia was detected in 121 patients (10.36%. Among them, 7 (0.59% patients were already having a diagnosis of respiratory failure, but were not on oxygen therapy while 5 (0.42% patients were having SpO 2 less than 90% despite of oxygen therapy. In 109 (9.34% patients, hypoxia was detected incidentally. Conclusion: Unnoticed hypoxia was detected in a significant number of the patients admitted in the wards of the hospital. Therefore, it is concluded that oxygen saturation measurements should be included with other vital parameters like pulse, temperature, and blood pressure, in the monitoring chart of all the admitted patients.

  9. Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

    Science.gov (United States)

    Hong, Beom-Ju; Kim, Jeongwoo; Jeong, Hoibin; Bok, Seoyeon; Kim, Young-Eun; Ahn, G-One

    2016-01-01

    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. PMID:28030900

  10. Potential for hypobaric storage as a phytosanitary treatment: mortality of Rhagoletis pomonella (Diptera: Tephritidae) in apples and effects on fruit quality.

    Science.gov (United States)

    Hulasare, Rajshekhar; Payton, Mark E; Hallman, Guy J; Phillips, Thomas W

    2013-06-01

    The efficacy of low-oxygen atmospheres using low pressure, referred to as hypobaric conditions, to kill egg and third-instar Rhagoletis pomonella (Walsh) in apples was investigated. Infested apples were exposed to 3.33 and 6.67 kPa in glass jars at 25 and 30 degrees C for times ranging from 3 to 120 h. Probit analyses and lethal dose ratio tests were performed to determine differences in lethal time values. Eggs were more tolerant of low pressure compared with third-instar R. pomonella. Mortality of eggs and larvae increased with increase in time of exposure to low pressure and temperature. Lower pressures increased percent mortality of eggs, but these values were not significantly different at the pressures tested in this investigation. The LT99 for R. pomonella eggs at 3.33 kPa was 105.98 and 51.46 h, respectively, at 25 and 30 degrees C, which was a significant effect of the higher temperature on egg mortality. Investigation into consumer acceptance of low-pressure-treated apples was done with 'Red Delicious' and 'Golden Delicious'. Apples exposed to 3.33 kPa at 25 and 30 degrees C for 3 and 5 d were stored at 1 degrees C for 2 wk and presented to a sensory panel for evaluation. The panelists rated treated apples with untreated controls for external and internal appearance and taste. Golden Delicious apples were unaffected for all three sensory factors across both temperatures and exposure times. Although taste was unaffected for Red Delicious, the internal and external appearances deteriorated. Use of low pressure for disinfestation and preservation of apples is a potential nonchemical alternative to chemical fumigants such as methyl bromide and phosphine.

  11. Acute hypoxia diminishes the relationship between blood pressure and subarachnoid space width oscillations at the human cardiac frequency

    Science.gov (United States)

    Wszedybyl-Winklewska, Magdalena; Wolf, Jacek; Swierblewska, Ewa; Kunicka, Katarzyna; Gruszecka, Agnieszka; Gruszecki, Marcin; Kucharska, Wieslawa; Winklewski, Pawel J.; Zabulewicz, Joanna; Guminski, Wojciech; Pietrewicz, Michal; Frydrychowski, Andrzej F.; Bieniaszewski, Leszek; Narkiewicz, Krzysztof

    2017-01-01

    Background Acute hypoxia exerts strong effects on the cardiovascular system. Heart-generated pulsatile cerebrospinal fluid motion is recognised as a key factor ensuring brain homeostasis. We aimed to assess changes in heart-generated coupling between blood pressure (BP) and subarachnoid space width (SAS) oscillations during hypoxic exposure. Methods Twenty participants were subjected to a controlled decrease in oxygen saturation (SaO2 = 80%) for five minutes. BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography, oxyhaemoglobin saturation with an ear-clip sensor, end-tidal CO2 with a gas analyser, and cerebral blood flow velocity (CBFV), pulsatility and resistive indices with Doppler ultrasound. Changes in SAS were recorded with a recently-developed method called near-infrared transillumination/backscattering sounding. Wavelet transform analysis was used to assess the relationship between BP and SAS oscillations. Results Gradual increases in systolic, diastolic BP and HR were observed immediately after the initiation of hypoxic challenge (at fifth minute +20.1%, +10.2%, +16.5% vs. baseline, respectively; all P<0.01), whereas SAS remained intact (P = NS). Concurrently, the CBFV was stable throughout the procedure, with the only increase observed in the last two minutes of deoxygenation (at the fifth minute +6.8% vs. baseline, P<0.05). The cardiac contribution to the relationship between BP and SAS oscillations diminished immediately after exposure to hypoxia (at the fifth minute, right hemisphere -27.7% and left hemisphere -26.3% vs. baseline; both P<0.05). Wavelet phase coherence did not change throughout the experiment (P = NS). Conclusions Cerebral haemodynamics seem to be relatively stable during short exposure to normobaric hypoxia. Hypoxia attenuates heart-generated BP SAS coupling. PMID:28241026

  12. Effects of Curcumin on Parameters of Myocardial Oxidative Stress and of Mitochondrial Glutathione Turnover in Reoxygenation after 60 Minutes of Hypoxia in Isolated Perfused Working Guinea Pig Hearts

    Directory of Open Access Journals (Sweden)

    Ermita I. Ibrahim Ilyas

    2016-01-01

    Full Text Available In cardiovascular surgery ischemia-reperfusion injury is a challenging problem, which needs medical intervention. We investigated the effects of curcumin on cardiac, myocardial, and mitochondrial parameters in perfused isolated working Guinea pig hearts. After preliminary experiments to establish the model, normoxia was set at 30 minutes, hypoxia was set at 60, and subsequent reoxygenation was set at 30 minutes. Curcumin was applied in the perfusion buffer at 0.25 and 0.5 μM concentrations. Cardiac parameters measured were afterload, coronary and aortic flows, and systolic and diastolic pressure. In the myocardium histopathology and AST in the perfusate indicated cell damage after hypoxia and malondialdehyde (MDA levels increased to 232.5% of controls during reoxygenation. Curcumin protected partially against reoxygenation injury without statistically significant differences between the two dosages. Mitochondrial MDA was also increased in reoxygenation (165% of controls, whereas glutathione was diminished (35.2% as well as glutathione reductase (29.3%, which was significantly increased again to 62.0% by 0.05 μM curcumin. Glutathione peroxidase (GPx was strongly increased in hypoxia and even more in reoxygenation (255% of controls. Curcumin partly counteracted this increase and attenuated GPx activity independently in hypoxia and in reoxygenation, 0.25 μM concentration to 150% and 0.5 μM concentration to 200% of normoxic activity.

  13. Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer

    DEFF Research Database (Denmark)

    Winther, Mette; Alsner, Jan; Sørensen, Brita Singers

    2016-01-01

    BACKGROUND/AIM: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). MATERIALS AND METHODS: microRNA expression changes induced by hypoxia in human GEC cell lines were...... associations of HRMs and clinical outcome in patients with GEC were identified. CONCLUSION: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM....

  14. 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.

  15. 低氧对大鼠前额叶皮层 AQP4蛋白和 HIF-1α蛋白表达的影响%Effect of Hypoxia on Expression of AQP4 and HIF-1αin Protein in Prefrontal Cortex of Rats

    Institute of Scientific and Technical Information of China (English)

    李敏; 董子玉; 陈学群

    2016-01-01

    Objective To investigate the expression of AQP4 and HIF-1 αprotein in the prefrontal cortex of SD rats under hypoxic conditions for the basis of elucidating the mechanism of hypoxic brain edema. Methods Twelve SD rats were randomly divided into the normal oxygen group and the hypoxia group.Rats in hypoxia group were exposed to hypoxia (7.8% O2 ,equal to 7 000 m altitude)in a hypobaric chamber for 8 h.The expression of AQP4 and HIF-1 αprotein in rat prefrontal cortex were determined by Western blot. Results AQP4 and HIF-1 α protein were enhanced in the hypoxic rat prefrontal cortex after exposure to 7 000 m hypoxia for 8 h (P <0.05)by Western blot. Conclusion The expression of AQP4 and HIF-1 αprotein in the prefrontal cortex of SD rats were increased after 8 h hypoxia.It was showed that HIF-1 might contribute to hypoxic brain edema by increasing the expression of AQP4 protein.%目的:探讨在低氧条件下 SD 大鼠前额叶皮层 AQP4蛋白和 HIF-1α蛋白的表达,为阐明低氧脑水肿的发病机制提供依据。方法将12只 SD 大鼠随机分为常氧组和低氧组,低氧组大鼠在低氧舱中模拟高原海拔7000 m 低氧(7.8% O2)中暴露8 h,通过 Western blot 检测大鼠前额叶皮层 AQP4蛋白和 HIF-1α蛋白的表达。结果在海拔7000 m 低氧暴露8 h 后,SD 大鼠前额叶皮层 AQP4蛋白和 HIF-1α蛋白表达增多(P <0.05)。结论SD 大鼠前额叶皮层 AQP4蛋白和 HIF-1α蛋白在模拟高原海拔7000 m 低氧8 h 后表达升高,提示 HIF-1可能通过上调 AQP4蛋白的表达参与了低氧脑水肿的发生。

  16. Hypoxia in models of lung cancer

    DEFF Research Database (Denmark)

    Graves, Edward E; Vilalta, Marta; Cecic, Ivana K

    2010-01-01

    PURPOSE: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer...... to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. EXPERIMENTAL DESIGN: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ......H2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. RESULTS: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping...

  17. Tracheal remodelling in response to hypoxia

    Science.gov (United States)

    Centanin, Lazaro; Gorr, Thomas A.; Wappner, Pablo

    2010-01-01

    The insect tracheal system is a continuous tubular network that ramifies into progressively thinner branches to provide air directly to every organ and tissue throughout the body. During embryogenesis the basic architecture of the tracheal system develops in a stereotypical and genetically controlled manner. Later, in larval stages, the tracheal system becomes plastic, and adapts to particular oxygen needs of the different tissues of the body. Oxygen sensing is mediated by specific prolyl-4-hydroxylases that regulate protein stability of the alpha subunit of oxygen-responsive transcription factors from the HIF family. Tracheal cells are exquisitely sensitive to oxygen levels, modulating the expression of hypoxia-inducible proteins that mediate sprouting of tracheal branches in direction to oxygen-deprived tissues. PMID:19482033

  18. Physiological Determinants of Human Acute Hypoxia Tolerance

    Science.gov (United States)

    2013-11-01

    45.72 ± 10.40 (25.30 – 70.43) Resting VO2 (ml/kg/min) 3.93 ± 0.90 (2.76 – 6.35) DLO2 (ml/mm Hg/min) 40.65 ± 7.72 (25.83 – 59.00) Total Hgb...less SpO2 fell during the 5-min exposure. Max velocity of MCA flow gradually increased after the start of the hypoxia exposure in all subjects and...Model C B SEB B t p Intercept -18.73 20.4 -9.18 .367 VO2 MAX (ml/min/kg) .027 -.200 .127 -.216 -1.57 .128 Heart Rate Variability (LF/HF) .221 .383

  19. 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...

  20. 2008 Fall 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...

  1. 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...

  2. An insight into tumoral hypoxia: the radiomarkers and clinical applications

    Directory of Open Access Journals (Sweden)

    Ana Margarida Abrantes

    2011-12-01

    Full Text Available Tumoral hypoxia is related to severe structural abnormalities of tumor microvessels, leading to deteriorated O2 diffusion. This decreased O2 concentration in cancer cells compromises cellular functions, besides being responsible for resistance to radiation therapy. Consequently, it is very important to know the hypoxic status of a tumor. In this review, the different methodologies available for evaluating cellular hypoxia in vivo are discussed, particularly those in which the hypoxia information is obtained through imaging. Among these the nuclear medicine approach uses ligands to complex with radionuclides. The resulting radioactive complexes which may be single photon or positron emitters, are very useful as imaging probes. The nature of ligands and their corresponding complexes, with application or potential application as hypoxia detectors, will be described. A summary of the most significant results so far obtained in clinical or preclinical applications will also be discussed.

  3. Historical records of coastal eutrophication-induced hypoxia

    Digital Repository Service at National Institute of Oceanography (India)

    Gooday, A; Jorissen, F.; Levin, L.A; Middelburg, J.J.; Naqvi, S.W.A; Rabalais, N.N; Scranton, M.; Zhang, J.

    Under certain conditions, sediment cores from coastal settings subject to hypoxia can yield records of environmental changes over time scales ranging from decades to millennia, sometimes with a resolution of as little as a few years. A variety...

  4. 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...

  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. 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...

  7. 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...

  8. 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...

  9. 2014 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...

  10. Local tissue hypoxia and formation of nasal polyps

    Institute of Scientific and Technical Information of China (English)

    姜舒; 董震; 朱冬冬; 杨占泉

    2003-01-01

    Objective To explore the response of nasal mucosa epithelial cells to hypoxia in terms of formation of nasal polyps (NP). Methods Epithelial cells of NP and inferior turbinate (IT) were cultured serum-fr ee under normal oxygen and hypoxic circumstances with stimulation of IL-1β and TNFα. The vascular endothelial growth factor (VEGF)mRNA and VEGF protein leve ls of the cultured cells were detected using in situ hybridization and ELISA, re spectively. Results The expression of VEGF mRNA was significantly higher in epithelial cells of NP t han in IT exposed to pro-inflammatory cytokines or hypoxia (P<0.01). VEGF levels were higher in NP epithelial cells than those of IT (P<0.01) under hypoxia.Conclusion VEGF-induced by hypoxia is very important for the early stages of forming polyps.

  11. Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

    OpenAIRE

    D'Alessandro, S.; Basilico, N.; Corbett, Y; Scaccabarozzi, D.; Omodeo-Salè, F.; Saresella, M.; Marventano, I.; Vaillant, M.; P. Olliaro; Taramelli, D

    2011-01-01

    Abstract Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumour mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched. This study aimed at assessing ...

  12. 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.

  13. 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

    2017-01-01

    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. PMID:28205556

  14. Influence of sustained hypoxia on the sensation of dyspnea.

    Science.gov (United States)

    Chonan, T; Okabe, S; Hida, W; Satoh, M; Kikuchi, Y; Takishima, T; Shirato, K

    1998-08-01

    We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

  15. 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.

  16. Macrophage-mediated response to hypoxia in disease

    Directory of Open Access Journals (Sweden)

    Tazzyman S

    2014-11-01

    Full Text Available Simon Tazzyman,1 Craig Murdoch,2 James Yeomans,1 Jack Harrison,1 Munitta Muthana3 1Department of Oncology, 2School of Clinical Dentistry, 3Department of Infection and Immunity, University of Sheffield, Sheffield, UK Abstract: Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment. Keywords: macrophage, hypoxia, inflammation, cytokine

  17. Carotid body oxygen sensing and adaptation to hypoxia.

    Science.gov (United States)

    López-Barneo, José; Macías, David; Platero-Luengo, Aida; Ortega-Sáenz, Patricia; Pardal, Ricardo

    2016-01-01

    The carotid body (CB) is the principal arterial chemoreceptor that mediates the hyperventilatory response to hypoxia. Our understanding of CB function and its role in disease mechanisms has progressed considerably in the last decades, particularly in recent years. The sensory elements of the CB are the neuron-like glomus cells, which contain numerous transmitters and form synapses with afferent sensory fibers. The activation of glomus cells under hypoxia mainly depends on the modulation of O2-sensitive K(+) channels which leads to cell depolarization and the opening of Ca(2+) channels. This model of sensory transduction operates in all mammalian species studied thus far, including man. However, the molecular mechanisms underlying the modulation of ion channel function by changes in the O2 level are as yet unknown. The CB plays a fundamental role in acclimatization to sustained hypoxia. Mice with CB atrophy or patients who have undergone CB resection due to surgical treatments show a marked intolerance to even mild hypoxia. CB growth under hypoxia is supported by the existence of a resident population of neural crest-derived stem cells of glia-like phenotype. These stem cells are not highly affected by exposure to low O2 tension; however, there are abundant synapse-like contacts between the glomus cells and stem cells (chemoproliferative synapses), which may be needed to trigger progenitor cell proliferation and differentiation under hypoxia. CB hypo- or hyper-activation may also contribute to the pathogenesis of several prevalent human diseases.

  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. Hypoxia and adipose tissue function and dysfunction in obesity.

    Science.gov (United States)

    Trayhurn, Paul

    2013-01-01

    The rise in the incidence of obesity has led to a major interest in the biology of white adipose tissue. The tissue is a major endocrine and signaling organ, with adipocytes, the characteristic cell type, secreting a multiplicity of protein factors, the adipokines. Increases in the secretion of a number of adipokines occur in obesity, underpinning inflammation in white adipose tissue and the development of obesity-associated diseases. There is substantial evidence, particularly from animal studies, that hypoxia develops in adipose tissue as the tissue mass expands, and the reduction in Po(2) is considered to underlie the inflammatory response. Exposure of white adipocytes to hypoxic conditions in culture induces changes in the expression of >1,000 genes. The secretion of a number of inflammation-related adipokines is upregulated by hypoxia, and there is a switch from oxidative metabolism to anaerobic glycolysis. Glucose utilization is increased in hypoxic adipocytes with corresponding increases in lactate production. Importantly, hypoxia induces insulin resistance in fat cells and leads to the development of adipose tissue fibrosis. Many of the responses of adipocytes to hypoxia are initiated at Po(2) levels above the normal physiological range for adipose tissue. The other cell types within the tissue also respond to hypoxia, with the differentiation of preadipocytes to adipocytes being inhibited and preadipocytes being transformed into leptin-secreting cells. Overall, hypoxia has pervasive effects on the function of adipocytes and appears to be a key factor in adipose tissue dysfunction in obesity.

  20. NITRIC OXIDE INTERFERES WITH HYPOXIA SIGNALING DURING COLONIC INFLAMMATION

    Directory of Open Access Journals (Sweden)

    Cintia Rabelo e Paiva CARIA

    2014-12-01

    Full Text Available Context Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs. Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. Objectives We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. Methods Colitis was induced by single (acute or repeated (reactivated colitis trinitrobenzenosulfonic acid administration in rats. In addition, one group of rats with reactivated colitis was also treated with Nw-Nitro-L-arginine methyl ester hydrochloride to block nitric oxide synthase. Colitis was assessed by macroscopic score and myeloperoxidase activity in the colon samples. Hypoxia was determined using the oxygen-dependent probe, pimonidazole. The expression of HIF-1α and HIF-induced factors (vascular endothelial growth factor - VEGF and apelin was assessed using Western blotting. Results The single or repeated administration of trinitrobenzenosulfonic acid to rats induced colitis which was characterized by a high macroscopic score and myeloperoxidase activity. Hypoxia was observed with both protocols. During acute colitis, HIF-1α expression was not increased, but VEGF and apelin were increased. HIF-1α expression was inhibited during reactivated colitis, and VEGF and apelin were not increased. Nw-Nitro-L-arginine methyl ester hydrochloride blockade during reactivated colitis restored HIF-1α, VEGF and apelin expression. Conclusions Nitric oxide could interfere with hypoxia signaling during reactivated colitis inflammation modifying the expression of proteins regulated by HIF-1α.

  1. Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols.

    Science.gov (United States)

    Lakatos, Kinga; Kalomoiris, Stefanos; Merkely, Béla; Nolta, Jan A; Fierro, Fernando A

    2016-02-01

    Mesenchymal stem cells (MSC) are currently being tested clinically for a plethora of conditions, with most approaches relying on the secretion of paracrine signals by MSC to modulate the immune system, promote wound healing, and induce angiogenesis. Hypoxia has been shown to affect MSC proliferation, differentiation, survival and secretory profile. Here, we investigate changes in the lipid composition of human bone marrow-derived MSC after exposure to hypoxia. Using mass spectrometry, we compared the lipid profiles of MSC derived from five different donors, cultured for two days in either normoxia (control) or hypoxia (1% oxygen). Hypoxia induced a significant increase of total triglycerides, fatty acids and diacylglycerols (DG). Remarkably, reduction of DG levels using the phosphatidylcholine-specific phospholipase C inhibitor D609 inhibited the secretion of VEGF and Angiopoietin-2, but increased the secretion of interleukin-8, without affecting significantly their respective mRNA levels. Functionally, incubation of MSC in hypoxia with D609 inhibited the potential of the cells to promote migration of human endothelial cells in a wound/scratch assay. Hence, we show that hypoxia induces in MSC an increase of DG that may affect the angiogenic potential of these cells.

  2. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    Science.gov (United States)

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-01

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity.

  3. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

    Directory of Open Access Journals (Sweden)

    Angelini Daniel J

    2013-01-01

    Full Text Available Abstract Background Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and role of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα in explaining this differential response. Methods We induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and challenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung vascular bed as well as HIMF expression and genomic analysis of whole lung. Results Chronic hypoxia increased both mean pulmonary artery pressure (mPAP and right ventricular (RV hypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary vessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and produced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung periphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently upregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the airway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in vascular tissue. Conclusions The results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen challenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of the lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the failure to develop PH in the allergic inflammation model.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Effects of hypoxia-inducible factor 1 on ischemic cerebrovascular disease

    Institute of Scientific and Technical Information of China (English)

    Yongjie Luo; Xiaoping Wang; Hongbin Sun

    2008-01-01

    Hypoxia-inducible factor I, a nuclear transcription factor, is induced by hypoxia. Hypoxia-inducible factor I, a heterodimeric DNA-binding protein, is composed of hypoxia-inducible factor 1α and hypoxia-inducible factor 1 β subunits, which are family members of the basic helix-loop-helix-PER, ARNT, SIM (PAS) protein. O2 concentration regulates hypoxia-inducible factor 1 activity via this subunit. Hypoxia-inducible factor 1α plays a major role in response to hypoxia and transcriptional activation, as well as in the target gene specificity of the DNA enhancer. Hypoxia-inducible factor 1β cannot be induced by hypoxia. This effect may be due to hypoxia-inducible factor 1 stability and activated conformation due to dimerization. Previous studies have shown that hypoxia-inducible factor 1 mRNA expression increases in the penumbra following ischemia/hypoxia. Hypoxia-inducible factor 1 plays an important role in brain tissue injury alter ischemia by affecting a series of target genes, elevating tolerance to hypoxia, and ensuring survival of neural cells. This article summarizes the structure, function, expression, regulatory mechanisms, biological effects, and significance of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease. As a transcriptional activator, hypoxia- inducible factor 1 plays a key role in hypoxic responses by stabilizing the internal environment. It also has been shown to regulate the expression of several genes. The regulatory effects of hypoxia-inducible factor 1 in patients with ischemic cerebrovascular disease have been described. The present review re-examined the concept of brain protection at the level of gene regulation.

  6. Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival

    Directory of Open Access Journals (Sweden)

    Joffrey ePelletier

    2012-02-01

    Full Text Available The hypoxia-inducible factor 1 (HIF-1, in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1, were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these hypoxia-preconditioned cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO2 acts as an alarm that prepares the cells to face subsequent nutrient depletion and to survive.

  7. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.

    Science.gov (United States)

    Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy; Wei, Mei; Beck, Thomas C; Volanakis, Emmanuel; Thomas, James W; Hiebert, Scott; Haase, Volker H; Boothby, Mark R

    2016-09-08

    Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

  8. Synovial tissue hypoxia and inflammation in vivo.

    LENUS (Irish Health Repository)

    Ng, C T

    2012-02-01

    INTRODUCTION: Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO(2)) in patients with inflammatory arthritis with macroscopic\\/microscopic inflammation and local levels of proinflammatory mediators. METHODS: Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO(2) under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta), interferon gamma (IFNgamma), IL6, macrophage inflammatory protein 3alpha (MIP3alpha) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. RESULTS: The tPO(2) was 22.5 (range 3.2-54.1) mm Hg and correlated inversely with macroscopic synovitis (r=-0.421, p=0.02), sublining CD3 cells (-0.611, p<0.01) and sublining CD68 cells (r=-0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO(2) in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor alpha (TNFalpha), IL1beta, IFNgamma and MIP3alpha in patients with tPO(2) <20 mm Hg (all p values <0.05). CONCLUSIONS: This is the first study to show a direct in vivo correlation between synovial tPO(2), inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

  9. The effect of ACE inhibition on the pulmonary vasculature in combined model of chronic hypoxia and pulmonary arterial banding in Sprague Dawley rats

    Science.gov (United States)

    Clarke, Shanelle; Baumgardt, Shelley; Molthen, Robert

    2010-03-01

    Microfocal CT was used to image the pulmonary arterial (PA) tree in rodent models of pulmonary hypertension (PH). CT images were used to measure the arterial tree diameter along the main arterial trunk at several hydrostatic intravascular pressures and calculate distensibility. High-resolution planar angiographic imaging was also used to examine distal PA microstructure. Data on pulmonary artery tree morphology improves our understanding of vascular remodeling and response to treatments. Angiotensin II (ATII) has been identified as a mediator of vasoconstriction and proliferative mitotic function. ATII has been shown to promote vascular smooth muscle cell hypertrophy and hyperplasia as well as stimulate synthesis of extracellular matrix proteins. Available ATII is targeted through angiotensin converting enzyme inhibitors (ACEIs), a method that has been used in animal models of PH to attenuate vascular remodeling and decrease pulmonary vascular resistance. In this study, we used rat models of chronic hypoxia to induce PH combined with partial left pulmonary artery occlusion (arterial banding, PLPAO) to evaluate effects of the ACEI, captopril, on pulmonary vascular hemodynamic and morphology. Male Sprague Dawley rats were placed in hypoxia (FiO2 0.1), with one group having underwent PLPAO three days prior to the chronic hypoxia. After the twenty-first day of hypoxia exposure, treatment was started with captopril (20 mg/kg/day) for an additional twenty-one days. At the endpoint, lungs were excised and isolated to examine: pulmonary vascular resistance, ACE activity, pulmonary vessel morphology and biomechanics. Hematocrit and RV/LV+septum ratio was also measured. CT planar images showed less vessel dropout in rats treated with captopril versus the non-treatment lungs. Distensibility data shows no change in rats treated with captopril in both chronic hypoxia (CH) and CH with PLPAO (CH+PLPAO) models. Hemodynamic measurements also show no change in the pulmonary vascular

  10. Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels.

    Science.gov (United States)

    Huang, Bo-Wen; Miyazawa, Masaki; Tsuji, Yoshiaki

    2014-12-01

    Cobalt chloride has been used as a hypoxia mimetic because it stabilizes hypoxia inducible factor-1α (HIF1-α) and activates gene transcription through a hypoxia responsive element (HRE). However, differences between hypoxia and hypoxia mimetic cobalt chloride in gene regulation remain elusive. Expression of ferritin, the major iron storage protein, is regulated at the transcriptional and posttranscriptional levels through DNA and RNA regulatory elements. Here we demonstrate that hypoxia and cobalt chloride regulate ferritin heavy chain (ferritin H) expression by two distinct mechanisms. Both hypoxia and cobalt chloride increased HIF1-α but a putative HRE in the human ferritin H gene was not activated. Instead, cobalt chloride but not hypoxia activated ferritin H transcription through an antioxidant responsive element (ARE), to which Nrf2 was recruited. Intriguingly, cobalt chloride downregulated ferritin H protein expression while it upregulated other ARE-regulated antioxidant genes in K562 cells. Further characterization demonstrated that cobalt chloride increased interaction between iron regulatory proteins (IRP1 and IRP2) and iron responsive element (IRE) in the 5'UTR of ferritin H mRNA, resulting in translational block of the accumulated ferritin H mRNA. In contrast, hypoxia had marginal effect on ferritin H transcription but increased its translation through decreased IRP1-IRE interaction. These results suggest that hypoxia and hypoxia mimetic cobalt chloride employ distinct regulatory mechanisms through the interplay between DNA and mRNA elements at the transcriptional and post-transcriptional levels.

  11. Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia

    Directory of Open Access Journals (Sweden)

    Debjani eTripathy

    2013-05-01

    Full Text Available Considerable evidence implicates hypoxia and vascular inflammation in Alzheimer’s disease (AD. Thrombin, a multifunctional inflammatory mediator, is demonstrable in the brains of AD patients both in the vessel walls and senile plaques. Hypoxia-inducible factor 1α (HIF-1α, a key regulator of the cellular response to hypoxia, is also upregulated in the vasculature of human AD brains. The objective of this study is to investigate inflammatory protein expression in the cerebrovasculature of transgenic AD mice and to explore the role of thrombin as a mediator of cerebrovascular inflammation and oxidative stress in AD and in hypoxia-induced changes in brain endothelial cells. Immunofluorescent analysis of the cerebrovasculature in AD mice demonstrates significant (p<0.01-0.001 increases in thrombin, HIF-1α, interleukin-6 (IL-6, monocyte chemoattractant protein-1 (MCP-1, matrix metalloproteinases (MMPs, and reactive oxygen species (ROS compared to controls. Administration of the thrombin inhibitor dabigatran (100 mg/kg to AD mice for 34 wks significantly decreases expression of inflammatory proteins and ROS. Exposure of cultured brain endothelial cells to hypoxia for 6 h causes an upregulation of thrombin, HIF-1α, MCP-1, IL-6 and MMP2 and ROS. Treatment of endothelial cells with the dabigatran (1 nM reduces ROS generation and inflammatory protein expression (p<0.01-0.001. The data demonstrate that inhibition of thrombin in culture blocks the increase in inflammatory protein expression and ROS generation evoked by hypoxia. Also, administration of dabigatran to transgenic AD mice diminishes expression of inflammatory proteins and ROS in the cerebromicrovasculature. Taken together, these results suggest that inhibiting thrombin generation could have therapeutic value in AD and other disorders where hypoxia, inflammation and oxidative stress are involved.

  12. 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.

  13. Quantifying hypoxia in human cancers using static PET imaging

    Science.gov (United States)

    Taylor, Edward; Yeung, Ivan; Keller, Harald; Wouters, Bradley G.; Milosevic, Michael; Hedley, David W.; Jaffray, David A.

    2016-11-01

    Compared to FDG, the signal of 18F-labelled hypoxia-sensitive tracers in tumours is low. This means that in addition to the presence of hypoxic cells, transport properties contribute significantly to the uptake signal in static PET images. This sensitivity to transport must be minimized in order for static PET to provide a reliable standard for hypoxia quantification. A dynamic compartmental model based on a reaction-diffusion formalism was developed to interpret tracer pharmacokinetics and applied to static images of FAZA in twenty patients with pancreatic cancer. We use our model to identify tumour properties—well-perfused without substantial necrosis or partitioning—for which static PET images can reliably quantify hypoxia. Normalizing the measured activity in a tumour voxel by the value in blood leads to a reduction in the sensitivity to variations in ‘inter-corporal’ transport properties—blood volume and clearance rate—as well as imaging study protocols. Normalization thus enhances the correlation between static PET images and the FAZA binding rate K 3, a quantity which quantifies hypoxia in a biologically significant way. The ratio of FAZA uptake in spinal muscle and blood can vary substantially across patients due to long muscle equilibration times. Normalized static PET images of hypoxia-sensitive tracers can reliably quantify hypoxia for homogeneously well-perfused tumours with minimal tissue partitioning. The ideal normalizing reference tissue is blood, either drawn from the patient before PET scanning or imaged using PET. If blood is not available, uniform, homogeneously well-perfused muscle can be used. For tumours that are not homogeneously well-perfused or for which partitioning is significant, only an analysis of dynamic PET scans can reliably quantify hypoxia.

  14. Dopamine does not limit fetal cerebrovascular responses to hypoxia.

    Science.gov (United States)

    Mayock, Dennis E; Bennett, Rachel; Robinson, Roderick D; Gleason, Christine A

    2007-01-01

    Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.

  15. Raisanberine protected pulmonary arterial rings and cardiac myocytes of rats against hypoxia injury by suppressing NADPH oxidase and calcium influx

    Institute of Scientific and Technical Information of China (English)

    Jie GAO; Yi-qun TANG; De-zai DAI; Yu-si CHENG; Guo-lin ZHANG; Can ZHANG; Yin DAI

    2012-01-01

    To investigate the protection of pulmonary arterial rings and cardiac myocytes of rats by raisanberine (RS),a derivative of berberine,against hypoxia injury and to elucidate the action mechanisms.Methods:Adult SD rats were exposed to intermittent hypoxia for 17 d or 28 d.The pulmonary arterial rings were isolated and vascular activity was measured using a transducer and computer-aided system.The difference in the tension produced by phenylephrine in the presence and absence of L-nitroarginine (10 μmol/L) was referred to as the NO bioavailability; the maximum release of NO was assessed by the ratio of the maximal dilatation caused by ACh to those caused by sodium nitroprusside.After the lungs were fixed,the internal and the external diameters of the pulmonary arterioles were measured using a graphic analysis system.Cultured cardiac myocytes from neonatal rats were exposed to H2O2 (10 μmol/L) to mimic hypoxia injury.ROS generation and [Ca2+]i level in the myocytes were measured using DHE and Fluo-3 fluorescence,respectively.Results:Oral administration of RS (80 mg/kg),the NADPH oxidase inhibitor apocynin (APO,80 mg/kg) or Ca2+ channel blocker nifedipine (Nif,10 mg/kg,) significantly alleviated the abnormal increase in the vasoconstriction force and endothelium-related vasodilatation induced by the intermittent hypoxia.The intermittent hypoxia markedly decreased the NO bioavailability and maximal NO release from pulmonary arterial rings,which were reversed by APO or RS administration.However,RS administration did not affect the NO bioavailability and maximal NO release from pulmonary arterial rings of normal rats.RS,Nif or APO administration significantly attenuated the pulmonary arteriole remodeling.Treatment of cultured cardiac myocytes with RS (10 μmol/L) suppressed the ROS generation and [Ca2+]i increase induced by H2O2,which were comparable to those caused by APO (10 μmol/L) or Nif (0.1 μmol/L).Conclusion:Raisanberine relieved hypoxic/oxidant insults to the

  16. 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

  17. miR-138 protects cardiomyocytes from hypoxia-induced apoptosis via MLK3/JNK/c-jun pathway

    Energy Technology Data Exchange (ETDEWEB)

    He, Siyi; Liu, Peng; Jian, Zhao; Li, Jingwei; Zhu, Yun; Feng, Zezhou; Xiao, Yingbin, E-mail: xiaoyb@vip.sina.com

    2013-11-29

    Highlights: •First time to find miR-138 is up-regulated in hypoxic cardiomyocytes. •First time to find miR-138 targets MLK3 and regulates JNK/c-jun pathway. •Rare myocardial biopsy of patients with CHD were collected. •Both silence and overexpression of miR-138 were implemented. •Various methods were used to detect cell function. -- Abstract: Cardiomyocytes experience a series of complex endogenous regulatory mechanisms against apoptosis induced by chronic hypoxia. MicroRNAs are a class of endogenous small non-coding RNAs that regulate cellular pathophysiological processes. Recently, microRNA-138 (miR-138) has been found related to hypoxia, and beneficial for cell proliferation. Therefore, we intend to study the role of miR-138 in hypoxic cardiomyocytes and the main mechanism. Myocardial samples of patients with congenital heart disease (CHD) were collected to test miR-138 expression. Agomir or antagomir of miR-138 was transfected into H9C2 cells to investigate its effect on cell apoptosis. Higher miR-138 expression was observed in patients with cyanotic CHD, and its expression gradually increased with prolonged hypoxia time in H9C2 cells. Using MTT and LDH assays, cell growth was significantly greater in the agomir group than in the negative control (NC) group, while antagomir decreased cell survival. Dual luciferase reporter gene and Western-blot results confirmed MLK3 was a direct target of miR-138. It was found that miR-138 attenuated hypoxia-induced apoptosis using TUNEL, Hoechst staining and Annexin V-PE/7-AAD flow cytometry analysis. We further detected expression of apoptosis-related proteins. In the agomir group, the level of pro-apoptotic proteins such as cleaved-caspase-3, cleaved-PARP and Bad significantly reduced, while Bcl-2 and Bcl-2/Bax ratio increased. Opposite changes were observed in the antagomir group. Downstream targets of MLK3, JNK and c-jun, were also suppressed by miR-138. Our study demonstrates that up-regulation of miR-138 plays

  18. Hypoxia Adjacent to the Mississippi River Plume

    Science.gov (United States)

    Rabalais, N. N.; Turner, R. E.

    2005-05-01

    The northern Gulf of Mexico receives the freshwater and constituent flux from the Mississippi River, which integrates 40% of the lower 48 United States. In the last half of the 20th century, the flux of nitrogen tripled, phosphorus concentration appears to have increased, and silicate concentration decreased. These changes result from landscape alterations over two centuries with an intensification of human activities that increased the flux of nitrogen and phosphorus particularly in the 1960s to 1980s. Evidence for eutrophication in the coastal ecosystem includes an increase in algal biomass, carbon accumulation from nutrient-enhanced production, worsening oxygen deficiency in the lower water column, and shifts in food web structure. The extent of the oxygen deficiency reaches 20,000 km2 of the inner continental shelf over long periods in summer with the potential for affecting commercially important fisheries in the Gulf. There is daily, weekly and seasonal variability in currents and stratification on the shelf and, therefore, no simple description of the couplings between nutrient delivery, carbon production in surface waters and delivery to and cycling in bottom waters. There are, however, multiple lines of evidence to implicate changes in riverine nutrient loads with overall primary and secondary production, carbon accumulation at the seabed, and low oxygen conditions on the shelf. The change in nutrient loads and responses of the northern Gulf coastal ecosystem, including widespread, severe seasonal hypoxia, parallel similar conditions in the coastal ocean on a global scale.

  19. Relaxin protects astrocytes from hypoxia in vitro.

    Directory of Open Access Journals (Sweden)

    Jordan M Willcox

    Full Text Available The peptide relaxin has recently been shown to protect brain tissues from the detrimental effects of ischemia. To date, the mechanisms for this remain unclear. In order to investigate the neuroprotective mechanisms by which relaxin may protect the brain, we investigated the possibility that relaxin protects astrocytes from hypoxia or oxygen/glucose deprivation (OGD. Cultured astrocytes were pre-treated with either relaxin-2 or relaxin-3 and exposed to OGD for 24 or 48 hours. Following OGD exposure, viability assays showed that relaxin-treated cells exhibited a higher viability when compared to astrocytes that experienced OGD-alone. Next, to test whether relaxin reduced the production of reactive oxygen species (ROS astrocytes were exposed to the same conditions as the previous experiment and a commercially available ROS detection kit was used to detect ROS production. Astrocytes that were treated with relaxin-2 and relaxin-3 showed a marked decrease in ROS production when compared to control astrocytes that were exposed only to OGD. Finally, experiments were performed to determine whether or not the mitochondrial membrane potential was affected by relaxin treatment during 24 hour OGD. Mitochondrial membrane potential was higher in astrocytes that were treated with relaxin-2 and relaxin-3 compared to untreated OGD-alone astrocytes. Taken together, these data present novel findings that show relaxin protects astrocytes from ischemic conditions through the reduction of ROS production and the maintenance of mitochondrial membrane potential.

  20. Eeffects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta of normoxic and chronic intermittent hypobaric hypoxic rats%黄连对正常氧和慢性间歇性低压低氧大鼠离体胸主动脉收缩活动的影响

    Institute of Scientific and Technical Information of China (English)

    张鹏; 宋士军; 刘威兰; 李连连; 赵卫丽; 张翼

    2011-01-01

    Objective: To observe the effects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta rings of normoxic and chronic intermittent hypobaric hypoxic(CIHH) rats, and to investigate the underlying mechanisms. Methods: Young male Sprague-Dawley rats were randomly divided into normoxic group and QHH group: the former were not given any special treatment; the latter were exposed to hypoxia in a hypobaric chamber simulating 5000 m altitude (PB = 404 mmHg, PO2= 84 mmHg, 11.1% O2), 6 hours daily for 28 days. The isolated thoracic aorta rings of rats were prepared and perfused in thermostat, and the effects of Coptis on vasoconstrictive activity of aorta rings were recorded, the mechanisms were investigated simultaneouly. Results: Coptis Chinensis significantly decreased NE and KCl-induced vaso-constriction of normoxic and QHH rats' isolated aortic rings, but the inhibitive effects had no obvious discrepancy between the two groups. The contractive amplitude had no marked change after the removal of endothelium. When calculated by Logit Loglinear analysis, IC50 of NE and KCl-induced contractive amplitude in normoxic group were respectively 2.99 g/L and 6.14 g/L, while they were 3.45 g/L and 5.81 g/L in CIHH group. The inhibitive effect of Coptis on vasoconstrictive activity of both groups could be partly decreased by Glibenclamide and nitro-L-arginine methyl ester; Indomethacin suppressed the effect on normoxic group as well. Also Coptis significantly inhibited NE-induced both intra-cellular and extracellular calciumion-depended vasoconstriction. Conclusion: Coptis Chinensis obviously relaxes isolated thoracic aorta rings of normoxic and CIHH rats, but the effects are endothelium-independent and have no marked discrepancy between the two groups. The mechanisms of the effects may be related to the opening of ATP-sensitive K+ channel, raise of nitric oxide concentration in both groups, and the increasing of PGI2 in normoxic group. Besides, Coptis may

  1. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury.

    Science.gov (United States)

    Kannan, Kolenkode B; Colorado, Iriana; Reino, Diego; Palange, David; Lu, Qi; Qin, Xiaofa; Abungu, Billy; Watkins, Anthony; Caputo, Francis J; Xu, Da-Zhong; Semenza, Gregg L; Deitch, Edwin A; Feinman, Rena

    2011-05-01

    Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gut-origin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxia-inducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1α-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1α deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1β mRNA levels. Furthermore, partial HIF-1α deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1α(+/-) mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1α protein levels nor caused significant gut and lung injury in wild-type or HIF-1α(+/-) mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.

  2. MUSCLE FIBER SPECIFIC ANTIOXIDATIVE SYSTEM ADAPTATION TO SWIM TRAINING IN RATS: INFLUENCE OF INTERMITTENT HYPOXIA

    Directory of Open Access Journals (Sweden)

    Olga Gonchar

    2005-06-01

    Full Text Available The aim of the present study was to examine the influence of intermittent hypoxia at rest and in combination with long-term high-intensity swimming exercise on lipid peroxidation and antioxidant defense system adaptation in skeletal muscles differing in fiber type composition. High-intensity chronic exercise was performed as swimming training with load that corresponded to ~ 75 % VO2max (30 min·day-1, 5 days·wk-1, for 4 wk. Intermittent hypoxic training (IHT consisted of repeated episodes of hypoxia (12%O2, 15 min, interrupted by equal periods of recovery (5 sessions/day, for 2 wk. Sessions of IHT were used during the first two weeks and during the last two weeks of chronic exercise. Oxidative (red gastrocnemius and soleus, mix and glycolytic (white gastrocnemius muscles were sampled. Our results indicated that high-intensity swim training in combination with sessions of IHT induced more profound antioxidative adaptations in skeletal muscles than the exercise training only. This adaptation has muscle fiber type specificity and is reflected in significantly elevated superoxide dismutase and catalase activities in highly oxidative muscle only. Training adaptation of GSH system (reduced glutathione content, activities of glutathione reductase, glutathione peroxidase, NADPH-supplying enzyme glucose-6-phosphate dehydrogenase occurred both in slow- and fast-twitch muscles. However, this process was more effective in oxidative muscles. IHT attenuated the increase in TBARS content induced by high-intensity swimming training. The test on exercise tolerance demonstrated a significant elevation of the swimming time to exhaustion after IHT at rest and after IHT in conjunction with high-intensity exercise in comparison with untrained and chronically exercised rats. These results confirmed that sessions of IHT might improve exercise tolerance and increase maximal work capacity

  3. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334 ameliorates murine colitis

    Directory of Open Access Journals (Sweden)

    Gupta R

    2014-01-01

    Full Text Available Ram Gupta,1 Anita R Chaudhary,2 Binita N Shah,1 Avinash V Jadhav,3 Shitalkumar P Zambad,1 Ramesh Chandra Gupta,4 Shailesh Deshpande,4 Vijay Chauthaiwale,4 Chaitanya Dutt4 1Department of Pharmacology, 2Cellular and Molecular Biology, 3Preclinical Safety Evaluation, 4Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India Background and aim: Mucosal healing in inflammatory bowel disease (IBD can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods: The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results: TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion: Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor

  4. Hypoxia adaptation and hemoglobin mutation in Tibetan chick embryo

    Institute of Scientific and Technical Information of China (English)

    GOU Xiao; LI Ning; LIAN Linsheng; YAN Dawei; ZHANG Hao; WU Changxin

    2005-01-01

    Tibetan chick lives at high altitudes between 2600 and 4200 m with a high hatchability and low land breeds survive rarely with a hatchability of 3.0% under hypoxia of simulated 4200 m. Under hypoxia of whole 21 d, the hatchability of Tibetan chick and Recessive White Feather broiler differed with a greatest disparity from day 4 to 11 and also significantly in other stages except from day 1 to 3. Hypoxia in each stage did not reduce significantly survival rate of this stage except hatchability. These two results indicated that the hypoxia in the early stage had an adverse effect on the later stage. All exons encoding chick hemoglobins were sequenced to analyze gene polymorphism. The functional mutation Met-32(B13)-Leu, related with hypoxia, was found in αD globin chain and the mutation frequency increased with increased altitude. In addition, under hypoxic conditions, the population with higher mutation frequency had a higher hatchability. The automated homology model building was carried out using crystal structure coordinates of chick HbD. The results indicated that the substitution Met-32(B13)-Leu provides a more hydrophobic environment which leads to higher stability of heme and oxygen affinity of hemoglobin. The occurrence of the mutation Met-32(B13)-Leu is related to the origin of Tibetan chick.

  5. Heart disease link to fetal hypoxia and oxidative stress.

    Science.gov (United States)

    Giussani, Dino A; Niu, Youguo; Herrera, Emilio A; Richter, Hans G; Camm, Emily J; Thakor, Avnesh S; Kane, Andrew D; Hansell, Jeremy A; Brain, Kirsty L; Skeffington, Katie L; Itani, Nozomi; Wooding, F B Peter; Cross, Christine M; Allison, Beth J

    2014-01-01

    The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

  6. Hypoxia promotes adipose-derived stem cell proliferation via VEGF

    Directory of Open Access Journals (Sweden)

    Phuc Van Pham

    2016-01-01

    Full Text Available Adipose-derived stem cells (ADSCs are a promising mesenchymal stem cell source with therapeutic applications. Recent studies have shown that ADSCs could be expanded in vitro without phenotype changes. This study aimed to evaluate the effect of hypoxia on ADSC proliferation in vitro and to determine the role of vascular endothelial growth factor (VEGF in ADSC proliferation. ADSCs were selectively cultured from the stromal vascular fraction obtained from adipose tissue in DMEM/F12 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic. ADSCs were cultured under two conditions: hypoxia (5% O2 and normal oxygen (21% O2. The effects of the oxygen concentration on cell proliferation were examined by cell cycle and doubling time. The expression of VEGF was evaluated by the ELISA assay. The role of VEGF in ADSC proliferation was studied by neutralizing VEGF with anti-VEGF monoclonal antibodies. We found that the ADSC proliferation rate was significantly higher under hypoxia compared with normoxia. In hypoxia, ADSCs also triggered VEGF expression. However, neutralizing VEGF with anti-VEGF monoclonal antibodies significantly reduced the proliferation rate. These results suggest that hypoxia stimulated ADSC proliferation in association with VEGF production. [Biomed Res Ther 2016; 3(1.000: 476-482

  7. Kidney EPO expression during chronic hypoxia in aged mice.

    Science.gov (United States)

    Benderro, Girriso F; LaManna, Joseph C

    2013-01-01

    In order to maintain normal cellular function, mammalian tissue oxygen concentrations must be tightly regulated within a narrow physiological range. The hormone erythropoietin (EPO) is essential for maintenance of tissue oxygen supply by stimulating red blood cell production and promoting their survival. In this study we compared the effects of 290 Torr atmospheric pressure on the kidney EPO protein levels in young (4-month-old) and aged (24-month-old) C57BL/6 mice. The mice were sacrificed after being anesthetized, and kidney samples were collected and processed by Western blot analysis. Relatively low basal expression of EPO during normoxia in young mice showed significant upregulation in hypoxia and stayed upregulated throughout the hypoxic period (threefold compared to normoxic control), showing a slight decline toward the third week. Whereas, a relatively higher normoxic basal EPO protein level in aged mice did not show significant increase until seventh day of hypoxia, but showed significant upregulation in prolonged hypoxia. Hence, we confirmed that there is a progressively increased accumulation of EPO during chronic hypoxia in young and aged mouse kidney, and the EPO upregulation during hypoxia showed a similarity with the pattern of increase in hematocrit, which we have reported previously.

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

    Science.gov (United States)

    Misra, Tvisha; Baccino-Calace, Martin; Meyenhofer, Felix; Rodriguez-Crespo, David; Akarsu, Hatice; Armenta-Calderón, Ricardo; Gorr, Thomas A.; Frei, Christian; Cantera, Rafael; Egger, Boris

    2017-01-01

    ABSTRACT 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. PMID:28011628

  9. Hypoxia and dehydroepiandrosterone in old age: a mouse survival study

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    Quillard Janine

    2006-12-01

    Full Text Available Abstract Background Survival remains an issue in pulmonary hypertension, a chronic disorder that often affects aged human adults. In young adult mice and rats, chronic 50% hypoxia (11% FIO2 or 0.5 atm induces pulmonary hypertension without threatening life. In this framework, oral dehydroepiandrosterone was recently shown to prevent and reverse pulmonary hypertension in rats within a few weeks. To evaluate dehydroepiandrosterone therapy more globally, in the long term and in old age, we investigated whether hypoxia decreases lifespan and whether dehydroepiandrosterone improves survival under hypoxia. Methods 240 C57BL/6 mice were treated, from the age of 21 months until death, by normobaric hypoxia (11% FIO2 or normoxia, both with and without dehydroepiandrosterone sulfate (25 mg/kg in drinking water (4 groups, N = 60. Survival, pulmonary artery and heart remodeling, weight and blood patterns were assessed. Results In normoxia, control mice reached the median age of 27 months (median survival: 184 days. Hypoxia not only induced cardiopulmonary remodeling and polycythemia in old animals but also induced severe weight loss, trembling behavior and high mortality (p Conclusion Dehydroepiandrosterone globally reduced what may be called an age-related frailty induced by hypoxic pulmonary hypertension. This interestingly recalls an inverse correlation found in the prospective PAQUID epidemiological study, between dehydroepiandrosterone blood levels and mortality in aged human smokers and former smokers.

  10. Predicted effects of climate change on northern Gulf of Mexico hypoxia

    Science.gov (United States)

    U.S. state and federal partners are working cooperatively to develop nutrient management strategies to reduce hypoxia (O2 Mexico. Numerical models that represent eutrophication and hypoxia development processes have been an important too...

  11. Skeletal muscle myofibrillar and sarcoplasmic protein synthesis rates are affected differently by altitude-induced hypoxia in native lowlanders

    DEFF Research Database (Denmark)

    Holm, Lars; Haslund, Mads Lyhne; Robach, Paul

    2010-01-01

    As a consequence to hypobaric hypoxic exposure skeletal muscle atrophy is often reported. The underlying mechanism has been suggested to involve a decrease in protein synthesis in order to conserve O(2). With the aim to challenge this hypothesis, we applied a primed, constant infusion of 1-(13)C-...

  12. Semiactive control for vibration attenuation

    Energy Technology Data Exchange (ETDEWEB)

    Leitmann, G. [Univ. of California, Berkeley, CA (United States). Coll. of Engineering

    1994-12-31

    With the advent of materials, such as electrorheological fluids, whose material properties can be altered rapidly by means of external stimuli, employing such materials as actuators for the controlled attenuation of undesirable vibrations is now possible. Such control schemes are dubbed semiactive in that they attenuate vibrations whether applied actively or passively. The author investigates various such control schemes, allowing for both separate and joint control of the stiffness and damping characteristics of the material.

  13. The effects of diel-cycling hypoxia acclimation on the hypoxia tolerance, swimming capacity and growth performance of southern catfish (Silurus meridionalis).

    Science.gov (United States)

    Yang, Han; Cao, Zhen-Dong; Fu, Shi-Jian

    2013-06-01

    To investigate the effects of diel-cycling hypoxia acclimation on the hypoxia tolerance, swimming and growth performance of juvenile southern catfish, we initially measured the critical oxygen tension (P(crit)), oxygen thresholds of aquatic surface respiration (ASR) and loss of equilibrium (LOE) of diel-cycling hypoxia-acclimated (15 d, 7:00-21:00, dissolved oxygen level (DO) = 7.0 ± 0.2 mg L(-1); 21:00-7:00, DO = 3.0 ± 0.2 mg L(-1)) and non-acclimated (15 d, DO = 7.0 ± 0.2 mg L(-1)) southern catfish at 25 °C. We then measured the critical swimming speed (U(crit)) and metabolic rate (MR) of hypoxia-acclimated and non-acclimated fish (under both hypoxic and normoxic conditions). The feeding rate (FR), feeding efficiency (FE) and specific growth rate (SGR) of fish in hypoxia-acclimated and non-acclimated groups were also measured. The P(crit), ASR and LOE of hypoxia-acclimated fish were significantly lower than those of non-acclimated fish. Hypoxia acclimation resulted in a significantly higher U(crit) when the individuals swam in hypoxia. The U(crit), maximum metabolic rate (MMR) and metabolic scope (MS) of both the hypoxia-acclimated and non-acclimated fish all decreased with the decrease of DO. However, the U(crit), MMR and MS decreased by 31, 43 and 54%, respectively, in non-acclimated fish, whereas these values decreased by 15, 28 and 29%, respectively, in hypoxia-acclimated fish, which suggests that hypoxia-acclimated fish were less sensitive to the DO decrease. The FR, FE and SGR all decreased by 21, 20 and 45%, respectively, in the hypoxia-acclimated group compared to the non-acclimated group. This result suggests that diel-cycling hypoxia acclimation improved the hypoxia tolerance and aerobic swimming performance of southern catfish, whereas impaired the growth performance. The high hypoxia tolerance and physiological plasticity to hypoxia-acclimated southern catfish may be related to its lower maintenance energy expenditure, sit-and-wait lifestyle and

  14. 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

  15. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.

    Science.gov (United States)

    Guise, Christopher P; Mowday, Alexandra M; Ashoorzadeh, Amir; Yuan, Ran; Lin, Wan-Hua; Wu, Dong-Hai; Smaill, Jeff B; Patterson, Adam V; Ding, Ke

    2014-02-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

  16. Bioreductive prodrugs as cancer therapeutics:targeting tumor hypoxia

    Institute of Scientific and Technical Information of China (English)

    Christopher P. Guise; Alexandra M. Mowday; Amir Ashoorzadeh; Ran Yuan; Wan-Hua Lin; Dong-Hai Wu; Jeff B. Smaill; Adam V. Patterson; Ke Ding

    2014-01-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cels in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracelular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

  17. Progressive multicystic encephalopathy: is there more than hypoxia-ischemia?

    Science.gov (United States)

    Garten, Lars; Hueseman, Dieter; Stoltenburg-Didinger, Gisela; Felderhoff-Mueser, Ursula; Weizsaecker, Katharina; Scheer, Ianina; Boltshauser, Eugen; Obladen, Michael

    2007-05-01

    Progressive multicystic encephalopathy following prenatal or perinatal hypoxia-ischemia is a well-described phenomenon in the literature. The authors report on a term infant with a devastating encephalopathy and severe neuronal dysfunction immediately after delivery without a known antecedent of prenatal or perinatal hypoxia or distress. Clinical and paraclinical findings in the patient are compared with those described in the literature. The authors focus on the specific results guiding to the final diagnosis of progressive multicystic encephalopathy and the timing of morphologic changes. As in this case, if the criteria of an acute hypoxic event sufficient to cause neonatal encephalopathy are not met, then factors other than hypoxia-ischemia may be leading to progressive multicystic encephalopathy.

  18. Susceptibility of dogs with heartworm disease to hypoxia.

    Science.gov (United States)

    Rawlings, C A; Losonsky, J M; Lewis, R E

    1977-09-01

    Dogs with Dirofilaria immitis microfilariae and early radiographic pulmonary artery changes, but without pulmonary hypertension or clinical signs of heartworm disease, were studied. An exaggerated pulmonary hypertensive response was found in these dogs if subjected to 10% inspired oxygen. The mean pulmonary artery pressure of control dogs was increased from base line (prehypoxia control) of 15.8 +/- 2.3 (SEM) mm of Hg to 20.2 +/- 2.3 during hypoxia, and the mean pulmonary pressure of dogs with heartworm disease increased from base line of 16.4 +/- 2.4 to 26.4 +/- 1.6 during hypoxia. Pulmonary blood flow was not affected by hypoxia indicating that the increased pulmonary artery pressure was the result of increased pulmonary vascular resistance. There was an individual variation of this pulmonary hypertensive response of dogs with heartworm disease that did not appear related to the severity of the pulmonary arterial lesions, as evaluated by pulmonary arteriography.

  19. Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer

    OpenAIRE

    2015-01-01

    Stromal fibrosis and tissue necrosis are major histological sequelae of hypoxia. The hypoxia-to-fibrosis sequence is well-documented in pancreatic ductal adenocarcinoma (PDAC). However, hypoxic and necrotic PDAC phenotypes are insufficiently characterized. Recently, reduction of tuberous sclerosis expression in mice together with oncogenic Kras demonstrated a rapidly metastasizing phenotype with histologically eccentric necrosis, transitional hypoxia and devascularisation. We established cell...

  20. Effects of post-resuscitation administration with sodium hydrosulfide on cardiac recovery in hypoxia-reoxygenated newborn piglets.

    Science.gov (United States)

    Cheung, Po-Yin; Miedzyblocki, Margaret; Lee, Tze-Fun; Bigam, David L

    2013-10-15

    Hydrogen sulfide may protect multiple organ systems against ischemic-reperfusion injuries. It is unknown if treatment with sodium hydrosulfide (NaHS, a hydrogen sulfide donor) will improve myocardial function and minimize oxidative stress in hypoxic-reoxygenated newborn piglets. Mixed breed piglets (1-5 day, 1.5-2.5 kg) were anesthetized and acutely instrumented for the measurement of systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics and blood gas parameters. The piglets were induced with normocapnic alveolar hypoxia (10-15% oxygen, 2h) followed by reoxygenation with 100% (1h) then 21% oxygen (3h). At 10 min of reoxygenation, either NaHS (10mg/kg, 5 ml) or saline (5 ml) was administered intravenously for 30 min (5 min bolus followed by 25 min of continuous infusion) in a blinded, block-randomized fashion (n = 7/group). Plasma lactate and troponin I levels and tissue markers of myocardial oxidative stress were also determined. Two hours hypoxia caused cardiogenic shock (45 ± 3% of respective normoxic baseline), reduced regional perfusion with metabolic acidosis (pH 6.94 ± 0.02). NaHS infusion significantly improved recovery of cardiac index (84 ± 3% vs. 72 ± 5% in controls), systemic oxygen delivery (84 ± 3% vs. 72 ± 5% in controls) and systemic oxygen consumption (102 ± 5% vs. 84 ± 6% in controls) at 4h of reoxygenation. NaHS had no significant effect on systemic and pulmonary blood pressures, regional blood flows, plasma lactate and troponin I levels. The myocardial glutathionine ratio was reduced in piglets treated with NaHS (vs. controls, P<0.05). Post-resuscitation administration of NaHS improves cardiac function and systemic perfusion and attenuates myocardial oxidative stress in newborn piglets following hypoxia-reoxygenation.

  1. Nitric Oxide And Hypoxia Response In Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Estefanía Caballano Infantes

    2015-08-01

    Full Text Available The expansion of pluripotent cells (ESCs and iPSCs under conditions that maintain their pluripotency is necessary to implement a cell therapy program. Previously, we have described that low nitric oxide (NO donor diethylenetriamine/nitric oxide adduct (DETA-NO added to the culture medium, promote the expansion of these cell types. The molecular mechanisms are not yet known. We present evidences that ESC and iPSCs in normoxia in presence of low NO triggers a similar response to hypoxia, thus maintaining the pluripotency. We have studied the stability of HIF-1α (Hypoxia Inducible Factor in presence of low NO. Because of the close relationship between hypoxia, metabolism, mitochondrial function and pluripotency we have analyzed by q RT-PCR the expression of genes involved in the glucose metabolism such as: HK2, LDHA and PDK1; besides other HIF-1α target gene. We further analyzed the expression of genes involved in mitochondrial biogenesis such as PGC1α, TFAM and NRF1 and we have observed that low NO maintains the same pattern of expression that in hypoxia. The study of the mitochondrial membrane potential using Mito-Tracker dye showed that NO decrease the mitochondrial function. We will analyze other metabolic parameters, to determinate if low NO regulates mitochondrial function and mimics Hypoxia Response. The knowledge of the role of NO in the Hypoxia Response and the mechanism that helps to maintain self-renewal in pluripotent cells in normoxia, can help to the design of culture media where NO could be optimal for stem cell expansion in the performance of future cell therapies.

  2. Heat shock response and mammal adaptation to high elevation (hypoxia)

    Institute of Scientific and Technical Information of China (English)

    WANG Xiaolin; XU Cunshuan; WANG Xiujie; WANG Dongjie; WANG Qingshang; ZHANG Baochen

    2006-01-01

    The mammal's high elevation (hypoxia) adaptation was studied by using the immunological and the molecular biological methods to understand the significance of Hsp (hypoxia) adaptation in the organic high elevation, through the mammal heat shock response. (1) From high elevation to low elevation (natural hypoxia): Western blot and conventional RT-PCR and real-time fluorescence quota PCR were adopted. Expression difference of heat shock protein of 70 (Hsp70) and natural expression of brain tissue of Hsp70 gene was determined in the cardiac muscle tissue among the different elevation mammals (yak). (2)From low elevation to high elevation (hypoxia induction):The mammals (domestic rabbits) from the low elevation were sent directly to the areas with different high elevations like 2300, 3300 and 5000 m above sea level to be raised for a period of 3 weeks before being slaughtered and the genetic inductive expression of the brain tissue of Hsp70 was determined with RT-PCR. The result indicated that all of the mammals at different elevations possessed their heat shock response gene. Hsp70 of the high elevation mammal rose abruptly under stress and might be induced to come into being by high elevation (hypoxia). The speedy synthesis of Hsp70 in the process of heat shock response is suitable to maintain the cells' normal physiological functions under stress. The Hsp70 has its threshold value. The altitude of 5000 m above sea level is the best condition for the heat shock response, and it starts to reduce when the altitude is over 6000 m above sea level. The Hsp70 production quantity and the cell hypoxia bearing capacity have their direct ratio.

  3. Impaired response of mature adipocytes of diabetic mice to hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seok Jong, E-mail: seok-hong@northwestern.edu; Jin, Da P.; Buck, Donald W.; Galiano, Robert D.; Mustoe, Thomas A., E-mail: tmustoe@nmh.org

    2011-10-01

    Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes.

  4. Skeletal muscle vasodilation during systemic hypoxia in humans.

    Science.gov (United States)

    Dinenno, Frank A

    2016-01-15

    In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite significant reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that 1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; 2) PGs do not normally contribute to vascular tone during hypoxia, however, they do affect vascular tone when NO is inhibited; 3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and 4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, skeletal muscle blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts augmented vasodilation and hyperemia compared with control (normoxic) conditions by ∼50%; however, in contrast to hypoxia alone, the response is not abolished, suggesting that other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release, or nitrite reduction to NO, or both likely play a role in regulating this response.

  5. Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics

    Science.gov (United States)

    Graves, Edward E.; Vilalta, Marta; Cecic, Ivana K.; Erler, Janine T.; Tran, Phuoc T.; Felsher, Dean; Sayles, Leanne; Sweet-Cordero, Alejandro; –Thu Le, Quynh; Giaccia, Amato J.

    2010-01-01

    Purpose In order to efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer in order to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. Experimental Design Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA) positron emission tomography (PET), and post-mortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. Results Minimal FAZA and pimonidazole accumulation was seen in tumors growing within the lungs, while subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types. Conclusions These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and anti-hypoxic cell therapies. PMID:20858837

  6. Past Occurrences of Hypoxia in the Baltic Sea

    Science.gov (United States)

    Zillen, L.; Conley, D. J.; Bjorck, S.

    2007-12-01

    The hypoxic zone in the Baltic Sea has increased in area by about four times since 1950. Widespread oxygen deficiency below the halocline has severely reduced macro benthic communities in the Baltic Proper and the Gulf of Finland over the past decades and negatively effected food chain dynamics, fish habitats and fisheries in the entire Baltic Sea. In addition, hypoxia alters nutrient biogeochemical cycles. The cause of the increased hypoxia is believed to be enhanced eutrophication through increased anthropogenic input of nutrients, such as phosphorous and nitrogen. Conditions prior to the 1950s are considered as the benchmark and some authors suggest that the earlier Baltic Sea was an oligothrophic, clear-water body with oxygenated deep waters. By contrast, studies of short sediment cores reveal that hypoxia has been present in some of the deepest basins for at least the last 100-200 years. In addition, long sediment cores suggest that hypoxia in the Baltic Sea has occurred intermittently in deep basins over the last c. 8500 years. Thus, the occurrence of present day hypoxia in the deeper basins need not necessarily be attributed to human activity but rather to natural oceanographic, geologic and climate conditions. We present a compilation of previous publications that reported the occurrence of laminated sediments (i.e. a palaeo-proxy for hypoxia) in the Baltic Sea. This review shows that the deeper parts of the Baltic Sea have experienced either intermittent or more regular hypoxia during most of the Holocene and that more continuous laminations started to form c. 7800-8500 cal. yr BP ago, in association with the establishment of a permanent halocline during the transition from the Ancylus Lake to the Littorina Sea. Laminated sediments were more common during the early and late Holocene and coincided with intervals of high organic productivity (high TOC content) and high salinity during the Holocene Thermal Maximum and the Medieval Climate Optimum. This study

  7. Clinical significance of hypoxia in nasopharyngeal carcinoma with a focus on existing and novel hypoxia molecular imaging.

    Science.gov (United States)

    Yip, Connie; Cook, Gary J R; Wee, Joseph; Fong, Kam Weng; Tan, Terence; Goh, Vicky

    2016-04-01

    Locally advanced nasopharyngeal carcinoma (NPC) is still associated with significant locoregional failure and poor overall survival (OS) after chemoradiation. The maximal therapeutic effect of conventional chemotherapy combined with radiation may have been reached and there is a clinical need to identify additional adverse prognostic factors that could be targeted therapeutically. Hypoxia, a known prognostic factor in head and neck cancers is an attractive target in NPC with various treatment strategies available such as hypoxic cell sensitisers/cytotoxins and increasing intratumoral oxygen delivery, to overcome the poorer outcomes associated with this phenotype. Thus, we aim to review the clinical significance of hypoxia as well as the current and future of molecular hypoxia imaging in NPC.

  8. Inhibition of Hypoxia-Induced Cell Motility by p16 in MDA-MB-231 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Liyuan Li, Yi Lu

    2010-01-01

    Full Text Available Our previous studies indicated that p16 suppresses breast cancer angiogenesis and metastasis, and downregulates VEGF gene expression by neutralizing the transactivation of the VEGF transcriptional factor HIF-1α. Hypoxia stimulates tumor malignant progression and induces HIF-1α. Because p16 neutralizes effect of HIF-1α and attenuates tumor metastatic progression, we intended to investigate whether p16 directly affects one or more aspects of the malignant process such as adhesion and migration of breast cancer cells. To approach this aim, MDA-MB-231 and other breast cancer cells stably transfected with Tet-on inducible p16 were used to study the p16 effect on growth, adhesion and migration of the cancer cells. We found that p16 inhibits breast cancer cell proliferation and migration, but has no apparent effect on cell adhesion. Importantly, p16 inhibits hypoxia-induced cell migration in breast cancer in parallel with its inhibition of HIF-1α transactivation activity. This study suggests that p16's ability to suppress tumor metastasis may be partially resulted from p16's inhibition on cell migration, in addition to its known functions on inhibition of cell proliferation, angiogenesis and induction of apoptosis.

  9. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression.

    Science.gov (United States)

    Fallone, F; Britton, S; Nieto, L; Salles, B; Muller, C

    2013-09-12

    Tumor cells adaptation to severe oxygen deprivation (hypoxia) plays a major role in tumor progression. The transcription factor HIF-1 (hypoxia-inducible factor 1), whose α-subunit is stabilized under hypoxic conditions is a key component of this process. Recent studies showed that two members of the phosphoinositide 3-kinase-related kinases (PIKKs) family, ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), regulate the hypoxic-dependent accumulation of HIF-1. These proteins initiate cellular stress responses when DNA damage occurs. In addition, it has been demonstrated that extreme hypoxia induces a replicative stress resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (ataxia telangiectasia and Rad3 related protein), another member of the PIKKs family. Here, we show that even less severe hypoxia (0.1% O2) also induces activation of ATR through replicative stress. Importantly, in using either transiently silenced ATR cells, cells expressing an inactive form of ATR or cells exposed to an ATR inhibitor (CGK733), we demonstrate that hypoxic ATR activation positively regulates the key transcription factor HIF-1 independently of the checkpoint kinase Chk1. We show that ATR kinase activity regulates HIF-1α at the translational level and we find that the elements necessary for the regulation of HIF-1α translation are located within the coding region of HIF-1α mRNA. Finally, by using three independent cellular models, we clearly show that the loss of ATR expression and/or kinase activity results in the decrease of HIF-1 DNA binding under hypoxia and consequently affects protein expression levels of two HIF-1 target genes, GLUT-1 and CAIX. Taken together, our data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1α translation. Our work offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic

  10. Adenosine triphosphate-sensitive potassium channel opener protects PC12 cells against hypoxia-induced apoptosis through PI3K/Akt and Bcl-2 signaling pathways

    Institute of Scientific and Technical Information of China (English)

    Hong Zhang; Chunhong Jia; Danyang Zhao; Yang Lu; Runling Wang; Jia Li

    2010-01-01

    Although previous studies have shown the neuroprotective effects of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener against ischemic neuronal damage, little is known about the mechanisms involved. Phosphatidylinositol-3 kinase (PI3K)/v-akt murine thy-moma viral oncogene homolog (Akt) and Bcl-2 are thought to be important factors that mediate neuroprotection. The present study investigated the effects of KATP openers on hypoxia-induced PC12 cell apoptosis, as well as mRNA and protein expression of Akt and Bcl-2. Results demon-strated that pretreatment of PC12 cells with pinacidil, a KATP opener, resulted in decreased PC12 cell apoptosis following hypoxia, as detected by Annexin-V fluorescein isothiocyanate/ propidium iodide double staining flow cytometry. In addition, mRNA and protein expression of phosphorylated Akt (p-Akt) and Bcl-2 increased, as detected by immunofluorescence, Western blot analysis, and reverse-transcription polymerase chain reaction. The protective effect of this preconditioning was attenuated by glipizide, a selective KATP blocker. These results demonstrate for the first time that the protective mechanisms of KATP openers on PC12 cell apoptosis following hypoxia could result from activation of the PI3K/Akt signaling pathway, which further activates expression of the downstream Bcl-2 gene.

  11. Photoacoustic Imaging Taking into Account Attenuation

    CERN Document Server

    Kowar, Richard

    2010-01-01

    First, we review existing attenuation models and discuss their causality properties, which we believe to be essential for algorithms for inversion with attenuated data. Then, we survey causality properties of common attenuation models. We also derive integro-differential equations which the attenuated waves are satisfying. In addition we discuss the ill--conditionness of the inverse problem for calculating the unattenuated wave from the attenuated one.

  12. Attenuation in Superconducting Circular Waveguides

    Directory of Open Access Journals (Sweden)

    K. H. Yeap

    2016-09-01

    Full Text Available We present an analysis on wave propagation in superconducting circular waveguides. In order to account for the presence of quasiparticles in the intragap states of a superconductor, we employ the characteristic equation derived from the extended Mattis-Bardeen theory to compute the values of the complex conductivity. To calculate the attenuation in a circular waveguide, the tangential fields at the boundary of the wall are first matched with the electrical properties (which includes the complex conductivity of the wall material. The matching of fields with the electrical properties results in a set of transcendental equations which is able to accurately describe the propagation constant of the fields. Our results show that although the attenuation in the superconducting waveguide above cutoff (but below the gap frequency is finite, it is considerably lower than that in a normal waveguide. Above the gap frequency, however, the attenuation in the superconducting waveguide increases sharply. The attenuation eventually surpasses that in a normal waveguide. As frequency increases above the gap frequency, Cooper pairs break into quasiparticles. Hence, we attribute the sharp rise in attenuation to the increase in random collision of the quasiparticles with the lattice structure.

  13. The clinical impact of hypoxia-regulated gene expression in loco-regional gastroesophageal cancer

    DEFF Research Database (Denmark)

    Winther, M.; Alsner, J.; Tramm, T.

    2015-01-01

    Purpose/Objective: In a former study (1), the hypoxia gene expression classifier, developed in head and neck squamous cell carcinomas, was applied in 89 patients with loco-regional gastroesophageal cancer (GC). Analysis of the 15 genes was indicative of hypoxia being more profound in esophagus...... and display greater heterogeneity compared to AC. However, previous indications that the hypoxia classifier might hold prognostic significance in ESCC patients could not be confirmed. Ongoing work includes in vitro studies of esophageal cancer cell lines in order to identify alternative hypoxia induced genes...... and to further explore the prognostic value of hypoxia in patients with loco-regional gastroesophageal cancer. (Figure Presented)....

  14. Assessment of hypoxia-inducible factor-1α mRNA expression in mantis shrimp as a biomarker of environmental hypoxia exposure.

    Science.gov (United States)

    Kodama, Keita; Rahman, Md Saydur; Horiguchi, Toshihiro; Thomas, Peter

    2012-04-23

    Efforts to assess the ecological impacts of the marked increase in coastal hypoxia worldwide have been hampered by a lack of biomarkers of hypoxia exposure in marine benthic organisms. Here, we show that hypoxia-inducible factor-1α (HIF-1α) transcript levels in the heart and cerebral ganglion of mantis shrimp (Oratosquilla oratoria) collected from hypoxic sites in Tokyo Bay are elevated several-fold over those in shrimp collected from normoxic sites. Upregulation of HIF-1α mRNA levels in the heart after exposure to sub-lethal hypoxia was confirmed in controlled laboratory experiments. HIF-1α transcript levels were increased at approximately threefold after 7 and 14 days of hypoxia exposure and declined to control levels within 24 h of restoration to normoxic conditions. The results provide the first evidence for upregulation of HIF-1α transcript levels in two hypoxia-sensitive organs, heart and cerebral ganglion, in a marine invertebrate exposed to environmental hypoxia. These results suggest that upregulation of HIF-1α transcript levels is an important component in adaptation of mantis shrimp to chronic hypoxia and is a potentially useful biomarker of environmental hypoxia exposure.

  15. Hypoxia-inducible factor 3 biology: complexities and emerging themes.

    Science.gov (United States)

    Duan, Cunming

    2016-02-15

    The hypoxia-inducible factor (HIF) family has three distinct members in most vertebrates. All three HIFs consist of a unique and oxygen-labile α-subunit and a common and stable β-subunit. While HIF-1 and HIF-2 function as master regulators of the transcriptional response to hypoxia, much less is known about HIF-3. The HIF-3α gene gives rise to multiple HIF-3α variants due to the utilization of different promoters, different transcription initiation sites, and alternative splicing. These HIF-3α variants are expressed in different tissues, at different developmental stages, and are differentially regulated by hypoxia and other factors. Recent studies suggest that different HIF-3α variants have different and even opposite functions. There is strong evidence that full-length HIF-3α protein functions as an oxygen-regulated transcription activator and that it activates a unique transcriptional program in response to hypoxia. Many HIF-3α target genes have been identified. While some short HIF-3α variants act as dominant-negative regulators of HIF-1/2α actions, other HIF-3α variants can inhibit HIF-1/2α actions by competing for the common HIF-β. There are also a number of HIF-3α variants yet to be explored. Future studies of these naturally occurring HIF-3α variants will provide new and important insights into HIF biology and may lead to the development of new therapeutic strategies.

  16. Hypoxia impairs visual acuity in snapper (Pagrus auratus).

    Science.gov (United States)

    Robinson, Esme; Jerrett, Alistair; Black, Suzanne; Davison, William

    2013-07-01

    We investigated the effect of environmental hypoxia on vision in snapper (Pagrus auratus). Juvenile snapper inhabit estuarine environments where oxygen conditions fluctuate on a seasonal basis. Optomotor experiments demonstrated that visual acuity is impaired by environmental hypoxia, but not until levels approach the critical oxygen tension (P crit) of this species (around 25% air-saturated seawater). In 100, 80, and 60% air-saturated seawater, a positive optomotor response was present at a minimum separable angle (M SA) of 1°. In 40% air-saturated seawater, vision was partially impaired with positive responses at M SAs of 2° and above. However, in 25% air-saturated seawater, visual acuity was seriously impaired, with positive responses only present at M SAs of 6° and above. Snapper were found to possess a choroid rete, facilitating the maintenance of high ocular oxygen partial pressures (PO2) during normoxia and moderate hypoxia (PO2, between 269 and 290 mmHg). However, at 40 and 25% water oxygen saturation, ocular PO2 was reduced to below 175 mmHg, which is perhaps linked to impairment of visual acuity in these conditions. The ability to preserve visual function during moderate hypoxia is beneficial for the maintenance of a visual lifestyle in the fluctuating oxygen environments of estuaries.

  17. Hypoxia-regulated microRNAs in human cancer

    Institute of Scientific and Technical Information of China (English)

    Guomin SHEN; Xiaobo LI; Yong-feng JIA; Gary A PIAZZA; Yaguang XI

    2013-01-01

    Hypoxia plays an important role in the tumor microenvironment by allowing the development and maintenance of cancer cells,but the regulatory mechanisms by which tumor cells adapt to hypoxic conditions are not yet well understood.MicroRNAs are recognized as a new class of master regulators that control gene expression and are responsible for many normal and pathological cellular processes.Studies have shown that hypoxia inducible factor 1 (HIF1) regulates a panel of microRNAs,whereas some of microRNAs target HIF1.The interaction between microRNAs and HIF1 can account for many vital events relevant to tumorigenesis,such as angiogenesis,metabolism,apoptosis,cell cycle regulation,proliferation,metastasis,and resistance to anticancer therapy.This review will summarize recent findings on the roles of hypoxia and microRNAs in human cancer and illustrate the machinery by which microRNAs interact with hypoxia in tumor cells,It is expected to update our knowledge about the regulatory roles of microRNAs in regulating tumor microenvironments and thus benefit the development of new anticancer drugs.

  18. [Thermal dissipation pathway in cucumber seedling leaves under hypoxia stress].

    Science.gov (United States)

    Jia, Yong-xi; Sun, Jin; Wang, Li-ping; Shu, Sheng; Guo, Shi-rong

    2011-03-01

    A water culture experiment was conducted to study the relationship between photosynthetic thermal dissipation and xanthophyll cycle in cucumber seedling leaves under hypoxia stress (the dissolved oxygen concentration in nutrient solution was 0.9-1.1 mg x L(-1)). Under the hypoxia stress, there was a significant decrease in the quantum yield of PS II photochemistry rate (phi(PS II)), net photosynthetic rate (Pn) under saturation light intensity, quanta yield (AQY), and maximal photochemical efficiency (Fv/Fm), suggesting that the photoinhibition of the seedling leaves was induced. Meanwhile, the thermal dissipation (NPQ) and the allocation of dissipation energy (D) by antenna increased, but the photochemical quenching apparent (q(p)) decreased, suggesting the enhancement of thermal dissipation in cucumber leaves under hypoxia stress. A positive correlation was observed between NPQ and xanthophyll de-epoxidation state (DEPS), and both of them were promoted by ascorbic acid (AsA) and inhibited by 1,4-dithiothreitol (DTT), suggesting that xanthophyll cycle was the major pathway of photosynthetic thermal dissipation in cucumber seedling leaves under hypoxia stress.

  19. Screening of hypoxia-inducible genes in sporadic ALS.

    LENUS (Irish Health Repository)

    Cronin, Simon

    2008-10-01

    Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.

  20. Combinatorial MicroRNAs Suppress Hypoxia-Induced Cardiomyocytes Apoptosis

    Directory of Open Access Journals (Sweden)

    Yingqi Xu

    2015-09-01

    Full Text Available Background/Aims: Our previous in silico analysis revealed potential synergy in the activities of micro(miRNAs in myocardial infarction. The present study investigated whether miR-1 and -21 act synergistically to protect against cardiomyocytes apoptosis. Methods: Cell survival was analyzed with cell viability assay; apoptosis was detected by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling, and the caspase-3 activity assay; and protein expression level was determined by western blotting. Results: MiR-1:miR-21 and several other miRNA pairs were evaluated for their potentially synergistic effects against myocardial hypoxia in neonatal rat ventricular cardiomyocytes. Lower combination indices suggested that miRNA pairs acted synergistically to inhibit apoptosis; miR-1 and -21 jointly blocked hypoxia-induced cardiomyocytes apoptosis. Moreover, combined application of miR-1 and -21 activated Akt and blocked hypoxia-induced upregulation of p53 in these cells. Conclusion: MiR-1 and -21 exert synergistic effects against hypoxia-induced cardiomyocytes apoptosis. These results provide a basis for the development of combined miRNA-based therapeutics to treat cardiovascular diseases.

  1. Epo deficiency alters cardiac adaptation to chronic hypoxia.

    Science.gov (United States)

    El Hasnaoui-Saadani, Raja; Marchant, Dominique; Pichon, Aurélien; Escoubet, Brigitte; Pezet, Mylène; Hilfiker-Kleiner, Denise; Hoch, Melanie; Pham, Isabelle; Quidu, Patricia; Voituron, Nicolas; Journé, Clément; Richalet, Jean-Paul; Favret, Fabrice

    2013-04-01

    The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAg(h)) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O2T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O2T remained lower than in WT mice. In CHx Epo-TAg(h) mice, LV hypertrophy, CO and O2T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAg(h) mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues.

  2. Human skin hypoxia modulates cerebrovascular and autonomic functions.

    Directory of Open Access Journals (Sweden)

    Olivia Pucci

    Full Text Available Because the skin is an oxygen sensor in amphibians and mice, we thought to confirm this function also in humans. The human upright posture, however, introduces additional functional demands for the maintenance of oxygen homeostasis in which cerebral blood flow and autonomic nervous system (ANS function may also be involved. We examined nine males and three females. While subjects were breathing ambient air, at sea level, we changed gases in a plastic body-bag during two conditions of the experiment such as to induce skin hypoxia (with pure nitrogen or skin normoxia (with air. The subjects performed a test of hypoxic ventilatory drive during each condition of the experiment. We found no differences in the hypoxic ventilatory drive tests. However, ANS function and cerebral blood flow velocities were modulated by skin hypoxia and the effect was significantly greater on the left than right middle cerebral arteries. We conclude that skin hypoxia modulates ANS function and cerebral blood flow velocities and this might impact life styles and tolerance to ambient hypoxia at altitude. Thus the skin in normal humans, in addition to its numerous other functions, is also an oxygen sensor.

  3. Hypoxia, Color Vision Deficiencies, and Blood Oxygen Saturation

    Science.gov (United States)

    2013-11-01

    Kobrick, 1970; Ernest & Krill, 1971; Kobrick, Zwick , Witt, & Devine,1984; Connolly & Barbur, 2009; Connolly, 2011). With the exception of two studies...Physiol, 28, 741-747. Kobrick, J.L., Zwick , H., Witt, C.E., & Devine, J.A. (1984). Effects of extended hypoxia on night vision. Aviat Space Environ Med

  4. Oxidative DNA damage and repair in skeletal muscle of humans exposed to high-altitude hypoxia

    DEFF Research Database (Denmark)

    Lundby, Carsten; Pilegaard, Henriette; van Hall, Gerrit;

    2003-01-01

    Recent research suggests that high-altitude hypoxia may serve as a model for prolonged oxidative stress in healthy humans. In this study, we investigated the consequences of prolonged high-altitude hypoxia on the basal level of oxidative damage to nuclear DNA in muscle cells, a major oxygen......-consuming tissue. Muscle biopsies from seven healthy humans were obtained at sea level and after 2 and 8 weeks of hypoxia at 4100 m.a.s.l. We found increased levels of strand breaks and endonuclease III-sensitive sites after 2 weeks of hypoxia, whereas oxidative DNA damage detected by formamidopyrimidine DNA......) was unaltered by prolonged hypoxia, in accordance with the notion that HO-1 is an acute stress response protein. In conclusion, our data indicate high-altitude hypoxia may serve as a good model for oxidative stress and that antioxidant genes are not upregulated in muscle tissue by prolonged hypoxia despite...

  5. X-Ray Attenuation Cell

    Energy Technology Data Exchange (ETDEWEB)

    Ryutov, D.; Toor, A.

    2000-03-03

    To minimize the pulse-to-pulse variation, the LCLS FEL must operate at saturation, i.e. 10 orders of magnitude brighter spectral brilliance than 3rd-generation light sources. At this intensity, ultra-high vacuums and windowless transport are required. Many of the experiments, however, will need to be conducted at a much lower intensity thereby requiring a reliable means to reduce the x-ray intensity by many orders of magnitude without increasing the pulse-to-pulse variation. In this report we consider a possible solution for controlled attenuation of the LCLS x-ray radiation. We suggest using for this purpose a windowless gas-filled cell with the differential pumping. Although this scheme is easily realizable in principle, it has to be demonstrated that the attenuator can be made short enough to be practical and that the gas loads delivered to the vacuum line of sight (LOS) are acceptable. We are not going to present a final, optimized design. Instead, we will provide a preliminary analysis showing that the whole concept is robust and is worth further study. The spatial structure of the LCLS x-ray pulse at the location of the attenuator is shown in Fig. 1. The central high-intensity component, due to the FEL, has a FWHM of {approx}100 {micro}m. A second component, due to the undulator's broad band spontaneous radiation is seen as a much lower intensity ''halo'' with a FWHM of 1 mm. We discuss two versions of the attenuation cell. The first is directed towards a controlled attenuation of the FEL up to the 4 orders of magnitude in the intensity, with the spontaneous radiation halo being eliminated by collimators. In the second version, the spontaneous radiation is not sacrificed but the FEL component (as well as the first harmonic of the spontaneous radiation) gets attenuated by a more modest factor up to 100. We will make all the estimates assuming that the gas used in the attenuator is Xenon and that the energy of the FEL is 8.25 keV. At

  6. Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep.

    Science.gov (United States)

    Blood, Arlin B; Hunter, Christian J; Power, Gordon G

    2003-12-15

    Exposure of the fetal sheep to moderate to severe hypoxic stress results in both increased cortical blood flow and decreased metabolic rate. Using intravenous infusion of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist that is permeable to the blood brain barrier, we examine the role of adenosine A1 receptors in mediating cortical blood flow and metabolic responses to moderate hypoxia. The effects of DPCPX blockade are compared to controls as well as animals receiving intravenous 8-(p-sulfophenyl)-theophylline) (8-SPT), a non-selective adenosine receptor antagonist which has been found to be blood brain barrier impermeable. Laser Doppler flow probes, tissue PO2, and thermocouples were implanted in the cerebral cortices of near-term fetal sheep. Catheters were placed in the brachial artery and sagittal sinus vein for collection of samples for blood gas analysis. Three to seven days later responses to a 30-min period of fetal hypoxemia (arterial PO2 10-12 mmHg) were studied with administration of 8-SPT, DPCPX, or vehicle. Cerebral metabolic rate was determined by calculation of both brain heat production and oxygen consumption. In response to hypoxia, control experiments demonstrated a 42 +/- 7 % decrease in cortical heat production and a 35 +/- 10 % reduction in oxygen consumption. In contrast, DPCPX infusion during hypoxia resulted in no significant change in brain heat production or oxygen consumption, suggesting the adenosine A1 receptor is involved in lowering metabolic rate during hypoxia. The decrease in cerebral metabolic rate was not altered by 8-SPT infusion, suggesting that the response is not mediated by adenosine receptors located outside the blood brain barrier. In response to hypoxia, control experiments demonstrated a 35 +/- 7 % increase in cortical blood flow. DPCPX infusion did not change this increase in cortical blood flow, however 8-SPT infusion attenuated increases in flow, indicating that hypoxic

  7. Hypoxia-Induced Iron Accumulation in Oligodendrocytes Mediates Apoptosis by Eliciting Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Rathnasamy, Gurugirijha; Murugan, Madhuvika; Ling, Eng-Ang; Kaur, Charanjit

    2016-09-01

    This study was aimed at evaluating the role of increased iron accumulation in oligodendrocytes and its role in their apoptosis in the periventricular white matter damage (PWMD) following a hypoxic injury to the neonatal brain. In response to hypoxia, in the PWM, there was increased expression of proteins involved in iron acquisition, such as iron regulatory proteins (IRP1, IRP2) and transferrin receptor in oligodendrocytes. Consistent with this, following a hypoxic exposure, there was increased accumulation of iron in primary cultured oligodendrocytes. The increased concentration of iron within hypoxic oligodendrocytes was found to elicit ryanodine receptor (RyR) expression, and the expression of endoplasmic reticulum (ER) stress markers such as binding-immunoglobulin protein (BiP) and inositol-requiring enzyme (IRE)-1α. Associated with ER stress, there was reduced adenosine triphosphate (ATP) levels within hypoxic oligodendrocytes. However, treatment with deferoxamine reduced the increased expression of RyR, BiP, and IRE-1α and increased ATP levels in hypoxic oligodendrocytes. Parallel to ER stress there was enhanced reactive oxygen species production within mitochondria of hypoxic oligodendrocytes, which was attenuated when these cells were treated with deferoxamine. At the ultrastructural level, hypoxic oligodendrocytes frequently showed dilated ER and disrupted mitochondria, which became less evident in those treated with deferoxamine. Associated with these subcellular changes, the apoptosis of hypoxic oligodendrocytes was evident with an increase in p53 and caspase-3 expression, which was attenuated when these cells were treated with deferoxamine. Thus, the present study emphasizes that the excess iron accumulated within oligodendrocytes in hypoxic PWM could result in their death by eliciting ER stress and mitochondrial disruption.

  8. Tumor necrosis factor receptor-associated protein 1 improves hypoxia-impaired energy production in cardiomyocytes through increasing activity of cytochrome c oxidase subunit II.

    Science.gov (United States)

    Xiang, Fei; Ma, Si-Yuan; Zhang, Dong-Xia; Zhang, Qiong; Huang, Yue-Sheng

    2016-10-01

    Tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes against hypoxia, but the underlying mechanisms are not completely understood. In the present study, we used gain- and loss-of-function approaches to explore the effects of tumor necrosis factor receptor-associated protein 1 and cytochrome c oxidase subunit II on energy production in hypoxic cardiomyocytes. Hypoxia repressed ATP production in cultured cardiomyocytes, whereas overexpression of tumor necrosis factor receptor-associated protein 1 significantly improved ATP production. Conversely, knockdown of tumor necrosis factor receptor-associated protein 1 facilitated the hypoxia-induced decrease in ATP synthesis. Further investigation revealed that tumor necrosis factor receptor-associated protein 1 induced the expression and activity of cytochrome c oxidase subunit II, a component of cytochrome c oxidase that is important in mitochondrial respiratory chain function. Moreover, lentiviral-mediated overexpression of cytochrome c oxidase subunit II antagonized the decrease in ATP synthesis caused by knockdown of tumor necrosis factor receptor-associated protein 1, whereas knockdown of cytochrome c oxidase subunit II attenuated the increase in ATP synthesis caused by overexpression of tumor necrosis factor receptor-associated protein 1. In addition, inhibition of cytochrome c oxidase subunit II by a specific inhibitor sodium azide suppressed the ATP sy nthesis induced by overexpressed tumor necrosis factor receptor-associated protein 1. Hence, tumor necrosis factor receptor-associated protein 1 protects cardiomyocytes from hypoxia at least partly via potentiation of energy generation, and cytochrome c oxidase subunit II is one of the downstream effectors that mediates the tumor necrosis factor receptor-associated protein 1-mediated energy generation program.

  9. Cellular and developmental adaptations to hypoxia: a Drosophila perspective.

    Science.gov (United States)

    Romero, Nuria Magdalena; Dekanty, Andrés; Wappner, Pablo

    2007-01-01

    The fruit fly Drosophila melanogaster, a widely utilized genetic model, is highly resistant to oxygen starvation and is beginning to be used for studying physiological, developmental, and cellular adaptations to hypoxia. The Drosophila respiratory (tracheal) system has features in common with the mammalian circulatory system so that an angiogenesis-like response occurs upon exposure of Drosophila larvae to hypoxia. A hypoxia-responsive system homologous to mammalian hypoxia-inducible factor (HIF) has been described in the fruit fly, where Fatiga is a Drosophila oxygen-dependent HIF prolyl hydroxylase, and the basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins Sima and Tango are, respectively, the Drosophila homologues of mammalian HIF-alpha (alpha) and HIF-beta (beta). Tango is constitutively expressed regardless of oxygen tension and, like in mammalian cells, Sima is controlled at the level of protein degradation and subcellular localization. Sima is critically required for development in hypoxia, but, unlike mammalian model systems, it is dispensable for development in normoxia. In contrast, fatiga mutant alleles are all lethal; however, strikingly, viability to adulthood is restored in fatiga sima double mutants, although these double mutants are not entirely normal, suggesting that Fatiga has Sima-independent functions in fly development. Studies in cell culture and in vivo have revealed that Sima is activated by the insulin receptor (InR) and target-of-rapamycin (TOR) pathways. Paradoxically, Sima is a negative regulator of growth. This suggests that Sima is engaged in a negative feedback loop that limits growth upon stimulation of InR/TOR pathways.

  10. Historical records of coastal eutrophication-induced hypoxia

    Directory of Open Access Journals (Sweden)

    A. J. Gooday

    2009-08-01

    Full Text Available Under certain conditions, sediment cores from coastal settings subject to hypoxia can yield records of environmental changes over time scales ranging from decades to millennia, sometimes with a resolution of as little as a few years. A variety of biological and geochemical indicators (proxies derived from such cores have been used to reconstruct the development of eutrophication and hypoxic conditions over time. Those based on (1 the preserved remains of benthic organisms (mainly foraminiferans and ostracods, (2 sedimentary features (e.g. laminations and (3 sediment chemistry and mineralogy (e.g. presence of sulphides and redox-sensitive trace elements reflect conditions at or close to the seafloor. Those based on (4 the preserved remains of planktonic organisms (mainly diatoms and dinoflagellates, (5 pigments and lipid biomarkers derived from prokaryotes and eukaryotes and (6 organic C, N and their stable isotope ratios reflect conditions in the water column. However, the interpretation of these indicators is not straightforward. A central difficulty concerns the fact that hypoxia is strongly correlated with, and often induced by, organic enrichment caused by eutrophication, making it difficult to separate the effects of these phenomena in sediment records. The problem is compounded by the enhanced preservation in anoxic and hypoxic sediments of organic microfossils and biomarkers indicating eutrophication. The use of hypoxia-specific proxies, such as the trace metals molybdenum and rhenium and the bacterial biomarker isorenieratene, together with multi-proxy approaches, may provide a way forward. All proxies of bottom-water hypoxia are basically qualitative; their quantification presents a major challenge to which there is currently no satisfactory solution. Finally, it is important to separate the effects of natural ecosystem variability from anthropogenic effects. Despite these problems, in the absence of historical data for dissolved oxygen

  11. Historical records of coastal eutrophication-induced hypoxia

    Directory of Open Access Journals (Sweden)

    A. J. Gooday

    2009-02-01

    Full Text Available Under certain conditions, sediment cores from coastal settings subject to hypoxia can yield records of environmental changes over time scales ranging from decades to millennia, sometimes with a resolution of as little as a few years. A variety of biological and geochemical proxies derived from such cores have been used to reconstruct the development of eutrophication and hypoxic conditions over time. Proxies based on 1 the preserved remains of benthic organisms (mainly foraminiferans and ostracods, 2 sedimentary features (e.g. laminations and 3 sediment chemistry and mineralogy (e.g. presence of sulphides and redox-sensitive trace elements reflect conditions at or close to the seafloor. Those based on 4 the preserved remains of planktonic organisms (mainly diatoms and dinoflagellates, 5 pigments and lipid biomarkers derived from prokaryotes and eukaryotes and 6 organic C, N and their isotope values reflect conditions in the water column. However, the interpretation of these proxies is not straightforward. A central difficulty concerns the fact that hypoxia is strongly correlated with, and often induced by, organic enrichment (eutrophication, making it difficult to separate the effects of these phenomena in sediment records. The problem is compounded by the enhanced preservation in anoxic and hypoxic sediments of organic microfossils and biomarkers indicating eutrophication. The use of hypoxia-specific indicators, such as the trace metals molybdenum and rhenium and the bacterial biomarker isorenieratene, which have not been used often in historical studies, may provide a way forward. All proxies of bottom-water hypoxia are basically qualitative; their quantification presents a major challenge to which there is currently no satisfactory solution. Finally, it is important to separate the effects of natural ecosystem variability from anthropogenic effects. Despite these problems, in the absence of historical data for dissolved oxygen concentrations

  12. Attenuation in silica-based optical fibers

    DEFF Research Database (Denmark)

    Wandel, Marie Emilie

    2006-01-01

    In this thesis on attenuation in silica based optical fibers results within three main topics are reported. Spectral attenuation measurements on transmission fibers are performed in the wide wavelength range 290 nm – 1700 nm. The measured spectral attenuation is analyzed with special emphasis...... on absorption peaks in order to investigate the cause of an unusual high attenuation in a series of transmission fibers. Strong indications point to Ni2+ in octahedral coordination as being the cause of the high attenuation. The attenuation of fibers having a high core refractive index is analyzed and the cause...... of the high attenuation measured in such fibers is described as being due to scattering of light on fluctuations of the core diameter. A novel semi-empirical model for predicting the attenuation of high index fibers is presented. The model is shown to be able to predict the attenuation of high index fibers...

  13. Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia.

    Directory of Open Access Journals (Sweden)

    Linlin Chang

    Full Text Available In spite of the tremendous efforts dedicated to developing hypoxia-activated prodrugs, no agents yet have been approved for clinical therapy. In the present study, the hypoxic selective anti-cancer activity as well as the cellular target of a novel tirapazamine (TPZ analogue, 7-methyl-3-(3-chlorophenyl-quinoxaline-2-carbonitrile 1,4-dioxide (Q6 were investigated. Q6 implemented anti-cancer effects via poisoning topoisomerase II (topo II under hypoxia. Modified trapped in agarose DNA immunostaining (TARDIS assay showed more topo II-DNA cleavage complexes trapped by Q6 than TPZ at even lower concentration. In addition, by introducing ataxia-telangiectasia-mutated (ATM kinase inhibitors caffeine and KU-60019, we displayed that Q6-triggered apoptosis was attributed, at least partially, to DNA double-strand breaks generated by the topo II-targeting effect. Collectively, Q6 stood out for its better hypoxia-selectivity and topo II-poisoning than the parental compound TPZ. All these data shed light on the research of Q6 as a promising hypoxia-activated prodrug candidate for human hepatocellular carcinoma therapy.

  14. Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation.

    Science.gov (United States)

    Makarenko, Vladislav V; Usatyuk, Peter V; Yuan, Guoxiang; Lee, May M; Nanduri, Jayasri; Natarajan, Viswanathan; Kumar, Ganesh K; Prabhakar, Nanduri R

    2014-04-15

    The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.

  15. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma.

    Science.gov (United States)

    Teng, Hongming; Yang, Yazong; Wei, Hengyun; Liu, Zundong; Liu, Zhichao; Ma, Yanhong; Gao, Zixiang; Hou, Lin; Zou, Xiangyang

    2015-06-03

    Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.

  16. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma

    Directory of Open Access Journals (Sweden)

    Hongming Teng

    2015-06-01

    Full Text Available Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.

  17. Chronic intermittent hypoxia induces atherosclerosis by NF-κB-dependent mechanisms.

    Science.gov (United States)

    Song, D; Fang, G; Mao, S-Z; Ye, X; Liu, G; Gong, Y; Liu, S F

    2012-11-01

    Chronic intermittent hypoxia (CIH) causes atherosclerosis in mice fed a high cholesterol diet (HCD). The mechanisms by which CIH promotes atherosclerosis are incompletely understood. This study defined the mechanistic role of NF-κB pathway in CIH+HCD induced atherosclerosis. Wild type (WT) and mice deficient in the p50 subunit of NF-κB (p50-KO) were fed normal chow diet (ND) or HCD, and exposed to sham or CIH. Atherosclerotic lesions on the en face aortic preparation and cross-sections of aortic root were examined. In WT mice, neither CIH nor HCD exposure alone caused, but CIH+HCD caused evident atherosclerotic lesions on both preparations after 20weeks of exposure. WT mice on ND and exposed to CIH for 35.6weeks did not develop atherosclerotic lesions. P50 gene deletion diminished CIH+HCD induced NF-κB activation and abolished CIH+HCD induced atherosclerosis. P50 gene deletion inhibited vascular wall inflammation, reduced hepatic TNF-α level, attenuated the elevation in serum cholesterol level and diminished macrophage foam cell formation induced by CIH+HCD exposure. These results demonstrate that inhibition of NF-κB activation abrogates the activation of three major atherogenic mechanisms associated with an abolition of CIH+HCD induced atherosclerosis. NF-κB may be a central common pathway through which CIH+HCD exposure activates multiple atherogenic mechanisms, leading to atherosclerosis.

  18. Josephson tunnel junction microwave attenuator

    DEFF Research Database (Denmark)

    Koshelets, V. P.; Shitov, S. V.; Shchukin, A. V.

    1993-01-01

    A new element for superconducting electronic circuitry-a variable attenuator-has been proposed, designed, and successfully tested. The principle of operation is based on the change in the microwave impedance of a superconductor-insulator-superconductor (SIS) Josephson tunnel junction when dc bias...

  19. Compact plasmonic variable optical attenuator

    DEFF Research Database (Denmark)

    Leosson, Kristjan; Rosenzveig, Tiberiu; Hermannsson, Pétur Gordon

    2008-01-01

    We demonstrate plasmonic nanowire-based thermo-optic variable optical attenuators operating in the 1525-1625 nm wavelength range. The devices have a footprint as low as 1 mm, extinction ratio exceeding 40 dB, driving voltage below 3 V, and full modulation bandwidth of 1 kHz. The polarization...

  20. Doxycycline protects human intestinal cells from hypoxia/reoxygenation injury: Implications from an in-vitro hypoxia model.

    Science.gov (United States)

    Hummitzsch, Lars; Zitta, Karina; Berndt, Rouven; Kott, Matthias; Schildhauer, Christin; Parczany, Kerstin; Steinfath, Markus; Albrecht, Martin

    2017-04-15

    Intestinal ischemia/reperfusion (I/R) injury is a grave clinical emergency and associated with high morbidity and mortality rates. Based on the complex underlying mechanisms, a multimodal pharmacological approach seems necessary to prevent intestinal I/R injury. The antibiotic drug doxycycline, which exhibits a wide range of pleiotropic therapeutic properties, might be a promising candidate for also reducing I/R injury in the intestine. To investigate possible protective effects of doxycycline on intestinal I/R injury, human intestinal CaCo-2 cells were exposed to doxycycline at clinically relevant concentrations. In order to mimic I/R injury, CaCo-2 were thereafter subjected to hypoxia/reoxygenation by using our recently described two-enzyme in-vitro hypoxia model. Investigations of cell morphology, cell damage, apoptosis and hydrogen peroxide formation were performed 24h after the hypoxic insult. Hypoxia/reoxygenation injury resulted in morphological signs of cell damage, elevated LDH concentrations in the respective culture media (P<0.001) and increased protein expression of proapoptotic caspase-3 (P<0.05) in the intestinal cultures. These events were associated with increased levels hydrogen peroxide (P<0.001). Preincubation of CaCo-2 cells with different concentrations of doxycycline (5µM, 10µM, 50µM) reduced the hypoxia induced signs of cell damage and LDH release (P<0.001 for all concentrations). The reduction of cellular damage was associated with a reduced expression of caspase-3 (5µM, P<0.01; 10µM, P<0.01; 50µM, P<0.05), while hydrogen peroxide levels remained unchanged. In summary, doxycycline protects human intestinal cells from hypoxia/reoxygenation injury in-vitro. Further animal and clinical studies are required to prove the protective potential of doxycycline on intestinal I/R injury under in-vivo conditions.

  1. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  2. Stormwater Attenuation by Green Roofs

    Science.gov (United States)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.

    2014-12-01

    Innovative municipal stormwater management technologies are urgently required in urban centers. Inadequate stormwater management can lead to excessive flooding, channel erosion, decreased stream baseflows, and degraded water quality. A major source of urban stormwater is unused roof space. Green roofs can be used as a stormwater management tool to reduce roof generated stormwater and generally improve the quality of runoff. With recent legislation in some North American cities, including Toronto, requiring the installation of green roofs on large buildings, research on the effectiveness of green roofs for stormwater management is important. This study aims to assess the hydrologic response of an extensive sedum green roof in London, Ontario, with emphasis on the response to large precipitation events that stress municipal stormwater infrastructure. A green roof rapidly reaches field capacity during large storm events and can show significantly different behavior before and after field capacity. At field capacity a green roof has no capillary storage left for retention of stormwater, but may still be an effective tool to attenuate peak runoff rates by transport through the green roof substrate. The attenuation of green roofs after field capacity is linked to gravity storage, where gravity storage is the water that is temporarily stored and can drain freely over time after field capacity has been established. Stormwater attenuation of a modular experimental green roof is determined from water balance calculations at 1-minute intervals. Data is used to evaluate green roof attenuation and the impact of field capacity on peak flow rates and gravity storage. In addition, a numerical model is used to simulate event based stormwater attenuation. This model is based off of the Richards equation and supporting theory of multiphase flow through porous media.

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

    Directory of Open Access Journals (Sweden)

    N. N. Rabalais

    2010-02-01

    Full Text Available 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 (<2 mg L−1, or approximately 30% saturation can form, therefore, under "natural" conditions, and are more likely to occur in marine systems when the water residence time is extended, water exchange and ventilation are minimal, stratification occurs, and where carbon production and export to the bottom layer are relatively high. Hypoxia has occurred through geological time and naturally occurs in oxygen minimum zones, deep basins, eastern boundary upwelling systems, and fjords.

    Hypoxia development and continuation in many areas of the world's coastal ocean is accelerated by human activities, especially where nutrient loading increased in the Anthropocene. This higher loading set in motion a cascading set of events related to eutrophication. The formation of 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

  4. Xanthine oxidase mediates hypoxia-inducible factor-2α degradation by intermittent hypoxia.

    Directory of Open Access Journals (Sweden)

    Jayasri Nanduri

    Full Text Available Sleep-disordered breathing with recurrent apnea produces chronic intermittent hypoxia (IH. We previously reported that IH leads to down-regulation of HIF-2α protein via a calpain-dependent signaling pathway resulting in oxidative stress. In the present study, we delineated the signaling pathways associated with calpain-dependent HIF-2α degradation in cell cultures and rats subjected to chronic IH. Reactive oxygen species (ROS scavengers prevented HIF-2α degradation by IH and ROS mimetic decreased HIF-2α protein levels in rat pheochromocytoma PC12 cell cultures, suggesting that ROS mediate IH-induced HIF-2α degradation. IH activated xanthine oxidase (XO by increased proteolytic conversion of xanthine dehydrogenase to XO. ROS generated by XO activated calpains, which contributed to HIF-2α degradation by IH. Calpain-induced HIF-2α degradation involves C-terminus but not the N-terminus of the HIF-2α protein. Pharmacological blockade as well as genetic knock down of XO prevented IH induced calpain activation and HIF-2α degradation in PC12 cells. Systemic administration of allopurinol to rats prevented IH-induced hypertension, oxidative stress and XO activation in adrenal medulla. These results demonstrate that ROS generated by XO activation mediates IH-induced HIF-2α degradation via activation of calpains.

  5. Ultrastructural modifications in the mitochondria of hypoxia-adapted Drosophila melanogaster.

    Science.gov (United States)

    Perkins, Guy; Hsiao, Yu-hsin; Yin, Songyue; Tjong, Jonathan; Tran, My T; Lau, Jenna; Xue, Jin; Liu, Siqi; Ellisman, Mark H; Zhou, Dan

    2012-01-01

    Chronic hypoxia (CH) occurs under certain physiological or pathological conditions, including in people who reside at high altitude or suffer chronic cardiovascular or pulmonary diseases. As mitochondria are the predominant oxygen-consuming organelles to generate ATP through oxidative phosphorylation in cells, their responses, through structural or molecular modifications, to limited oxygen supply play an important role in the overall functional adaptation to hypoxia. Here, we report the adaptive mitochondrial ultrastructural modifications and the functional impacts in a recently generated hypoxia-adapted Drosophila melanogaster strain that survives severe, otherwise lethal, hypoxic conditions. Using electron tomography, we discovered increased mitochondrial volume density and cristae abundance, yet also cristae fragmentation and a unique honeycomb-like structure in the mitochondria of hypoxia-adapted flies. The homeostatic levels of adenylate and energy charge were similar between hypoxia-adapted and naïve control flies and the hypoxia-adapted flies remained active under severe hypoxia as quantified by negative geotaxis behavior. The equilibrium ATP level was lower in hypoxia-adapted flies than those of the naïve controls tested under severe hypoxia that inhibited the motion of control flies. Our results suggest that the structural rearrangement in the mitochondria of hypoxia-adapted flies may be an important adaptive mechanism that plays a critical role in preserving adenylate homeostasis and metabolism as well as muscle function under chronic hypoxic conditions.

  6. Ultrastructural modifications in the mitochondria of hypoxia-adapted Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Guy Perkins

    Full Text Available Chronic hypoxia (CH occurs under certain physiological or pathological conditions, including in people who reside at high altitude or suffer chronic cardiovascular or pulmonary diseases. As mitochondria are the predominant oxygen-consuming organelles to generate ATP through oxidative phosphorylation in cells, their responses, through structural or molecular modifications, to limited oxygen supply play an important role in the overall functional adaptation to hypoxia. Here, we report the adaptive mitochondrial ultrastructural modifications and the functional impacts in a recently generated hypoxia-adapted Drosophila melanogaster strain that survives severe, otherwise lethal, hypoxic conditions. Using electron tomography, we discovered increased mitochondrial volume density and cristae abundance, yet also cristae fragmentation and a unique honeycomb-like structure in the mitochondria of hypoxia-adapted flies. The homeostatic levels of adenylate and energy charge were similar between hypoxia-adapted and naïve control flies and the hypoxia-adapted flies remained active under severe hypoxia as quantified by negative geotaxis behavior. The equilibrium ATP level was lower in hypoxia-adapted flies than those of the naïve controls tested under severe hypoxia that inhibited the motion of control flies. Our results suggest that the structural rearrangement in the mitochondria of hypoxia-adapted flies may be an important adaptive mechanism that plays a critical role in preserving adenylate homeostasis and metabolism as well as muscle function under chronic hypoxic conditions.

  7. Intermittent hypoxia selects for genotypes and phenotypes that increase survival, invasion, and therapy resistance.

    Directory of Open Access Journals (Sweden)

    Daniel Verduzco

    Full Text Available Hypoxia in tumors correlates with greater risk of metastases, increased invasiveness, and resistance to systemic and radiation therapy. The evolutionary dynamics that links specific adaptations to hypoxia with these observed tumor properties have not been well investigated. While some tumor populations may experience fixed hypoxia, cyclical and stochastic transitions from normoxia to hypoxia are commonly observed in vivo. Although some phenotypic adaptations to this cyclic hypoxia are likely reversible, we hypothesize that some adaptations may become fixed through mutations promoted by hypoxia-induced genomic instability. Here we seek to identify genetic alterations and corresponding stable phenotypes that emerge following cyclic hypoxia. Although these changes may originate as adaptations to this specific environmental stress, their fixation in the tumor genome may result in their observation in tumors from regions of normoxia, a condition known as pseudohypoxia. We exposed several epithelial cell lines to 50 cycles of hypoxia-normoxia, followed by culture in normoxia over a period of several months. Molecular analyses demonstrated permanent changes in expression of several oncogenes and tumor-suppressors, including p53, E-cadherin, and Hif-1α. These changes were associated with increased resistance to multiple cytotoxins, increased survival in hypoxia and increased anchorage-independent growth. These results suggest cycles of hypoxia encountered in early cancers can select for specific and stable genotypic and phenotypic properties that persist even in normoxic conditions, which may promote tumor progression and resistance to therapy.

  8. Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.

    Directory of Open Access Journals (Sweden)

    Sung-Min Kim

    Full Text Available BACKGROUND: Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained can affect the loss of motor neurons or cognitive function in an in vivo model of ALS. OBJECTIVE: To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice. METHODS: Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation. RESULTS: Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation. CONCLUSIONS: Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in

  9. Ferrite attenuator modulation improves antenna performance

    Science.gov (United States)

    Hooks, J. C.; Larson, S. G.; Shorkley, F. H.; Williams, B. T.

    1970-01-01

    Ferrite attenuator inserted into appropriate waveguide reduces the gain of the antenna element which is causing interference. Modulating the ferrite attenuator to change the antenna gain at the receive frequency permits ground tracking until the antenna is no longer needed.

  10. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    Energy Technology Data Exchange (ETDEWEB)

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  11. Pim-2 protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via downregulation of Bim expression.

    Science.gov (United States)

    Xu, Yan; Xing, Yawei; Xu, Yanjie; Huang, Chahua; Bao, Huihui; Hong, Kui; Cheng, Xiaoshu

    2016-12-01

    We know that silencing Bim, a pro-apoptosis protein, significantly attenuates glucose and oxygen-deprived induced apoptosis in cardiomyocytes. However, the mechanisms underlying the regulation of the Bim activation in the heart have remained unknown. Pim-2 is one of three Pim serine/threonine kinase family members thought to be involved in cell survival and proliferation. H9c2 cardiomyocytes were subjected to a hypoxia/reoxygenation (H/R) condition in vitro, mimicking ischemic/reperfusion injury in vivo. H/R augmented the expression of Bim, Cyt C, and Pim-2 and induced H9c2 cell apoptosis. Overexpression of Pim-2 attenuated apoptosis which induced by H/R in H9c2 cells, via downregulation of Bim and Cyt C expression. Silencing of Pim-2 promoted H/R-induced apoptosis via upregulation of Bim and Cyt C expression. Co-IP revealed the interaction between Pim-2 and Bim protein, with Bim Ser(65) phosphorylated by Pim-2. Furthermore, blocking proteasome activity by MG132 prevented Bim degradation, and Bim S65A mutation could reverse the anti-apoptotic role of Pim-2 which induced by H/R. These data demonstrated that Pim-2 is a novel Bim-interacting protein, which negatively regulates Bim degradation and protects H9c2 cardiomyocytes from H/R-induced apoptosis.

  12. Differential Expression of Three Hypoxia-inducible Factor-α Subunits in Pulmonary Arteries of Rat with Hypoxia-induced Hypertension

    Institute of Scientific and Technical Information of China (English)

    Qi-Fang LI; Ai-Guo DAI

    2005-01-01

    Hypoxia inducible transcription factor (HIF)-1α plays an important role in the development of hypoxic pulmonary hypertension, but little is known about HIF-2α and HIF-3α with respect to transcriptional regulation by hypoxia. To examine the expression patterns of all HIF-α subunits (HIF-1α, HIF-2α and HIF-3α) in pulmonary arteries of rats undergoing systemic hypoxia, five groups of healthy male Wistar rats were exposed to normoxia (N) and hypoxia for 3 (H3), 7 (H7), 14 (H14) and 21 (H21) d respectively. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricular hypertrophy index were measured. Lungs were inflation fixed for immunohistochemistry and in situ hybridization, and homogenized for Western blot. mPAP increased significantly after 7 d of hypoxia [(18.4±0.4) vs. (14.4±0.4) mmHg, H7 vs.N], reached its peak after 14 d of hypoxia, then remained stable. Pulmonary artery remodeling and right ventricular hypertrophy developed significantly after 14 d of hypoxia. During normoxia, HIF-1 α and HIF-3α staining were slightly positive regarding mRNA levels. A substantial alteration of HIF-1 α and HIF-3α staining occurred in pulmonary arteries after 14 d and 7 d of hypoxia, respectively, but HIF-2α stainin g showed an inversed trend after 14 d of hypoxia. Protein levels of all HIF-α subunits except HIF-3α showed a marked increase corresponding to the duration of hypoxia, which was obtained by Western blot. Our study found that HIF-1 α, HIF-2α and HIF-3α may not only confer different target genes, but also play key pathogenetic roles in hypoxic-induced pulmonary hypertension.

  13. The Role of Hypoxia in Orthodontic Tooth Movement

    Directory of Open Access Journals (Sweden)

    A. Niklas

    2013-01-01

    Full Text Available Orthodontic forces are known to have various effects on the alveolar process, such as cell deformation, inflammation, and circulatory disturbances. Each of these conditions affecting cell differentiation, cell repair, and cell migration, is driven by numerous molecular and inflammatory mediators. As a result, bone remodeling is induced, facilitating orthodontic tooth movement. However, orthodontic forces not only have cellular effects but also induce vascular changes. Orthodontic forces are known to occlude periodontal ligament vessels on the pressure side of the dental root, decreasing the blood perfusion of the tissue. This condition is accompanied by hypoxia, which is known to either affect cell proliferation or induce apoptosis, depending on the oxygen gradient. Because upregulated tissue proliferation rates are often accompanied by angiogenesis, hypoxia may be assumed to fundamentally contribute to bone remodeling processes during orthodontic treatment.

  14. PHD2: from hypoxia regulation to disease progression.

    Science.gov (United States)

    Meneses, Ana M; Wielockx, Ben

    2016-01-01

    Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential.

  15. 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.

  16. Chlorine signal attenuation in concrete.

    Science.gov (United States)

    Naqvi, A A; Maslehuddin, M; ur-Rehman, Khateeb; Al-Amoudi, O S B

    2015-11-01

    The intensity of prompt gamma-ray was measured at various depths from chlorine-contaminated silica fume (SF) concrete slab concrete specimens using portable neutron generator-based prompt gamma-ray setup. The intensity of 6.11MeV chloride gamma-rays was measured from the chloride contaminated slab at distance of 15.25, 20.25, 25.25, 30.25 and 35.25cm from neutron target in a SF cement concrete slab specimens. Due to attenuation of thermal neutron flux and emitted gamma-ray intensity in SF cement concrete at various depths, the measured intensity of chlorine gamma-rays decreases non-linearly with increasing depth in concrete. A good agreement was noted between the experimental results and the results of Monte Carlo simulation. This study has provided useful experimental data for evaluating the chloride contamination in the SF concrete utilizing gamma-ray attenuation method.

  17. Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer.

    LENUS (Irish Health Repository)

    McEvoy, Lynda M

    2015-01-01

    Ovarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1α. While HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance.

  18. Hypoxia imaging using Positron Emission Tomography in non-small cell lung cancer: implications for radiotherapy.

    Science.gov (United States)

    Bollineni, Vikram Rao; Wiegman, Erwin M; Pruim, Jan; Groen, Harry J M; Langendijk, Johannes A

    2012-12-01

    Tumour hypoxia is an important contributor to radioresistance. Thus, increasing the radiation dose to hypoxic areas may result in improved locoregional tumour control. However, this strategy requires accurate detection of the hypoxic sub-volume using PET imaging. Secondly, hypoxia imaging may also provide prognostic information and may be of help to monitor treatment response. Therefore, a systematic review of the scientific literature was carried out on the use of Positron Emission Tomography (PET) to image Tumour hypoxia in non-small cell lung cancer (NSCLC). More specifically, the purpose of this review was (1) to summarize the different hypoxia tracers used, (2) to investigate whether Tumour hypoxia can be detected in NSCLC and finally (3) whether the presence of hypoxia can be used to predict outcome.

  19. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation.

    LENUS (Irish Health Repository)

    Garvey, J F

    2012-02-01

    There is increasing evidence that intermittent hypoxia plays a role in the development of cardiovascular risk in obstructive sleep apnoea syndrome (OSAS) through the activation of inflammatory pathways. The development of translational models of intermittent hypoxia has allowed investigation of its role in the activation of inflammatory mechanisms and promotion of cardiovascular disease in OSAS. There are noticeable differences in the response to intermittent hypoxia between body tissues but the hypoxia-sensitive transcription factors hypoxia-inducible factor-1 and nuclear factor-kappaB appear to play a key role in mediating the inflammatory and cardiovascular consequences of OSAS. Expanding our understanding of these pathways, the cross-talk between them and the activation of inflammatory mechanisms by intermittent hypoxia in OSAS will provide new avenues of therapeutic opportunity for the disease.

  20. Hypoxia reoxygenation induces premature senescence in neonatal SD rat cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    Feng-xiang ZHANG; Ming-long CHEN; Qi-jun SHAN; Jian-gang ZOU; Chun CHEN; Bing YANG; Dong-jie XU; Yu JIN; Ke-jiang CAO

    2007-01-01

    Aim: To investigate whether hypoxia reoxygenation induces premature senes-cence in neonatal Sprague-Dawley (SD) rat cardiomyocytes. Methods: Cardio-myocytes were isolated from neonatal SD rat heart and identified by immunohisto-chemistry. The control cultures were incubated at 37 ℃ in a humidified atmo-sphere of 5% CO and 95% air. The hypoxic cultures were incubated in a modular incubator chamber filled with 1% O2, 5% CO2, and balance N2 for 6 h. The reoxygen-ated cultures were subjected to 1% O2 and 5% CO2 for 6 h, then 21% oxygen for 4,8, 12, 24, and 48 h, respectively. Cell proliferation was determined using bromo-deoxyuridine labeling. The ultrastructure of cardiomyocytes was observed by using an electron microscope. Β-Galactosidase activity was determined by using a senescence β-galactosidase Staining Kit. P16INK4a and telomerase reverse tran-scriptase (TERT) mRNA levels were measured by real time quantitative PCR. TERT protein expression was determined by immunohistochemistry. Telomerase activi-ties were assayed by using the Telo TAGGG Telomerase PCR ELISApplus kit. Results:The initial cultures consisted of pure cardiomyocytes identified by immunohisto-chemistry. The proportion of BrdU positive cells was reduced significantly in the hypoxia reoxygenation-treated group (P<0.01). Under the condition of hypoxia reoxygenation, mitochondrial dehydration appeared; p16'INK4a and TERT mRNA levels, β-galactosidase activity, TERT protein expression and telomerase activi-ties were all significantly increased (P<0.01 or P<0.05). Conclusion: These data indicate that premature senescence could be induced in neonatal SD rat cardiomyo-cytes exposed to hypoxia reoxygenation. Although TERT significantly increased,it could not block senescence.

  1. Activation of the Astrocytic Endothelin System in Response to Hypoxia

    Institute of Scientific and Technical Information of China (English)

    An Ding Xua; Kai M.Schmidt-Ott; Scbastian Tuschick; Lutz Liefeldt; Susan Lyons; Helmut Kettcnmann; Martin.Paul

    2000-01-01

    Objcctive:To determine the gene expression patterns of endothelin (ET)system components in cultured astrocytes(AC),and to examine the direct effcct of hypoxia on ET system gene expression in cultured AC.Background:The ET system was considered to be related to the activation of AC. However,how hypoxia affects the ET system in transcriptional levels remains unclear.Methods:AC was prepared form mouse brain,and cultured 4 days.then further incubated under normoxic or hypoxic conditions for 24h. ET peptide levels were determined by RIA.The transcripts of ET system components were measured by Northern Blot RNA hybridization and RT-PCR.Results:In normoxic AC,ET-1,ET converting enzyme(ECE)-2,ETA receptor,and ETB receptor mRNAs were detected by Northern blot hybridization with ETB receptor mRNA appearing to be the predominant receptor transcript.ET-3and ECE-1 were only detected by RT-PCR,indicating low expression levels of these components.Hypoxia induced a 1.7-fold increase in ET peptide level in culture supernatants as comparcd to controls(p<0.001).At the same time,a 3-fold increase of ET-1 mRNA(p<0.001)was determined by Northern blot RNA analysis,indicating a regulation at the transcriptional Ievel.Both ETA and ETB receptor mRNASweredownregulated to approximately 20% of control levels(p<0.001), while ECE-2 mRNA remained unchanged.Conclusions:These results indicate direct effects of hypoxia on astrocytic ET system gene expression.Therefore,similar changes observed in ischemic conditions in vivo are likely to be at least partially independent from the modified cerebral microenvironment.

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

    Science.gov (United States)

    2011-01-01

    Critical Regulator of IronMetabolism during Hypoxia Korry J. Hintze1 and James P. McClung2 1Department of Nutrition , Dietetics & Food Sciences, Utah State...University, Logan, UT 84322, USA 2Military Nutrition Division, US Army Research Institute of Environmental Medicine (USARIEM), Natick, MA 01760, USA...through a series of cellular transport proteins that are sensitive to the recently discovered iron regulatory hormone, hepcidin. The discovery of

  3. Hypoxia-Inducible Factor as an Angiogenic Master Switch

    Science.gov (United States)

    Hashimoto, Takuya; Shibasaki, Futoshi

    2015-01-01

    Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications

  4. A theoretical stochastic control framework for adapting radiotherapy to hypoxia

    Science.gov (United States)

    Saberian, Fatemeh; Ghate, Archis; Kim, Minsun

    2016-10-01

    Hypoxia, that is, insufficient oxygen partial pressure, is a known cause of reduced radiosensitivity in solid tumors, and especially in head-and-neck tumors. It is thus believed to adversely affect the outcome of fractionated radiotherapy. Oxygen partial pressure varies spatially and temporally over the treatment course and exhibits inter-patient and intra-tumor variation. Emerging advances in non-invasive functional imaging offer the future possibility of adapting radiotherapy plans to this uncertain spatiotemporal evolution of hypoxia over the treatment course. We study the potential benefits of such adaptive planning via a theoretical stochastic control framework using computer-simulated evolution of hypoxia on computer-generated test cases in head-and-neck cancer. The exact solution of the resulting control problem is computationally intractable. We develop an approximation algorithm, called certainty equivalent control, that calls for the solution of a sequence of convex programs over the treatment course; dose-volume constraints are handled using a simple constraint generation method. These convex programs are solved using an interior point algorithm with a logarithmic barrier via Newton’s method and backtracking line search. Convexity of various formulations in this paper is guaranteed by a sufficient condition on radiobiological tumor-response parameters. This condition is expected to hold for head-and-neck tumors and for other similarly responding tumors where the linear dose-response parameter is larger than the quadratic dose-response parameter. We perform numerical experiments on four test cases by using a first-order vector autoregressive process with exponential and rational-quadratic covariance functions from the spatiotemporal statistics literature to simulate the evolution of hypoxia. Our results suggest that dynamic planning could lead to a considerable improvement in the number of tumor cells remaining at the end of the treatment course

  5. Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

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    Kemal Erdem Basaran

    Full Text Available Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m. Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.

  6. Restraint Stress Intensifies Interstitial K+ Accumulation during Severe Hypoxia

    Science.gov (United States)

    Schnell, Christian; Janc, Oliwia A.; Kempkes, Belinda; Callis, Carolina Araya; Flügge, Gabriele; Hülsmann, Swen; Müller, Michael

    2012-01-01

    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 3 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 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 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. PMID:22470344

  7. Effect of simulated high-altitude hypoxia on Porphyromonas gingivalis

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    Jing-jing HUANG

    2012-04-01

    Full Text Available Objective To investigate the effects of simulated high-altitude hypoxia on the detection rate and endotoxin level of Porphyromonas gingivalis (Pg of subgingival bacterial plagues in rabbit periodontitis models. Methods Forty male rabbits were randomly divided into four groups, namely, normoxia control group (group A1, normoxia experimental group (group A2, hypoxia control group (group B1, and hypoxia experimental group (group B2. Each group included 10 rabbits. Periodontitis models was established in groups A2 and B2 combined by ligating both lower central incisors with steel ligature and feeding periodontitis diets, and then the animals were housed in a hypoxia chamber (simulating 5000m altitude, 23h per day. Groups A1 and A2 were raised normal diet in normoxia environment. After eight weeks, the rabbit periodontitis model was evaluated by observing radiographic features of the X-ray films and histopathologic changes under a light microscope. Subgingival plague sample from periodontal pockets on both lower central incisors were collected for isolation, culture and identification of Pg, and for detection of the endotoxin level. Results The histopathologic observation and X-ray examination results showed that the periodontitis of rabbits in group B2 was significantly more severe than that in group A2. The detection rates of Pg in group A1, A2, B1 and B2 was 0%, 50%, 55% and 95% (P < 0.05. Pg detection rate and endotoxin level were higher in group B2 (95%, 0.46±0.04EU/ml than in group A2 (50%, 0.38±0.02EU/ml, P < 0.05. Conclusions The process speed and damage degree of periodontitis in hypoxic environment is higher than that in normoxic environment. Moreover, the hypoxic environment is more suitable in the colonization of Pg with higher endotoxin level in subgingival plague.

  8. Clinical study of diffusion hypoxia after nitrous oxide analgesia.

    OpenAIRE

    Quarnstrom, F. C.; Milgrom, P.; Bishop, M. J.; DeRouen, T. A.

    1991-01-01

    In order to estimate the incidence of diffusion hypoxia, arterial oxygen saturation was measured in 104 healthy adult dental patients who were administered nitrous oxide-oxygen analgesia and who did not receive postcessation oxygen. Pretreatment saturation levels as determined by pulse oximetry ranged from 93% to 100%. When the nitrous oxide-oxygen administration ceased, the saturation levels were from 95% to 100%. The mean saturation dropped about 2% over the next 4 min and then stabilized. ...

  9. Mechanisms of geometrical seismic attenuation

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    Igor B. Morozov

    2011-07-01

    Full Text Available In several recent reports, we have explained the frequency dependence of the apparent seismic quality-factor (Q observed in many studies according to the effects of geometrical attenuation, which was defined as the zero-frequency limit of the temporal attenuation coefficient. In particular, geometrical attenuation was found to be positive for most waves traveling within the lithosphere. Here, we present three theoretical models that illustrate the origin of this geometrical attenuation, and we investigate the causes of its preferential positive values. In addition, we discuss the physical basis and limitations of both the conventional and new attenuation models. For waves in media with slowly varying properties, geometrical attenuation is caused by variations in the wavefront curvature, which can be both positive (for defocusing and negative (for focusing. In media with velocity/density contrasts, incoherent reflectivity leads to geometrical-attenuation coefficients which are proportional to the mean squared reflectivity and are always positive. For «coherent» reflectivity, the geometrical attenuation is approximately zero, and the attenuation process can be described according to the concept of «scattering Q». However, the true meaning of this parameter is in describing the mean reflectivity within the medium, and not that of the traditional resonator quality factor known in mechanics. The general conclusion from these models is that non-zero and often positive levels of geometrical attenuation are common in realistic, heterogeneous media, both observationally and theoretically. When transformed into the conventional Q-factor form, this positive geometrical attenuation leads to Q values that quickly increase with frequency. These predictions show that the positive frequency-dependent Q observed in many datasets might represent artifacts of the transformations of the attenuation coefficients into Q.

  1. Late Holocene changes in hypoxia off the west coast of India: Micropalaeontological evidences

    Digital Repository Service at National Institute of Oceanography (India)

    Nigam, R.; Prasad, V.; Mazumder, A.; Garg, R.; Saraswat, R.; Henriques, P.J.

    . and Turner, R. E., Hypoxia in the northern Gulf of Mexico: description, causes and change. In Coastal Hypoxia: Consequences for Living Resources and Ecosystems (eds Rabalais, N. N. and Turner, R. E.), American Geophysical Union, New York, 2001, pp. 1.... In Modern Foraminifera (ed. Sen Gupta, B. K.), Kluwer, Great Britain, 1999, pp. 201–216. 30. Osterman, L. E., Benthic foraminifera from the continental shelf and slope of the Gulf of Mexico: an indicator of shelf hypoxia. Estuarine Coastal Shelf Sci...

  2. The mitochondrial respiratory chain is required for organismal adaptation to hypoxia

    OpenAIRE

    Robert B. Hamanaka; Samuel E. Weinberg; Colleen R. Reczek; Navdeep S. Chandel

    2016-01-01

    Hypoxia-inducible factors (HIFs) are crucial for cellular and organismal adaptation to hypoxia. The mitochondrial respiratory chain is the largest consumer of oxygen in most mammalian cells; however, it is unknown whether the respiratory chain is necessary for in vivo activation of HIFs and organismal adaptation to hypoxia. HIF-1 activation in the epidermis has been shown to be a key regulator of the organismal response to hypoxic conditions, including renal production of erythropoietin (Epo)...

  3. Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway?

    OpenAIRE

    Hemant Kumar; Dong-Kug Choi

    2015-01-01

    Oxygen homeostasis reflects the constant body requirement to generate energy. Hypoxia (0.1–1% O2), physioxia or physoxia (∼1–13%), and normoxia (∼20%) are terms used to define oxygen concentration in the cellular environment. A decrease in oxygen (hypoxia) or excess oxygen (hyperoxia) could be deleterious for cellular adaptation and survival. Hypoxia can occur under both physiological (e.g., exercise, embryonic development, underwater diving, or high altitude) and pathological conditions (e.g...

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

    Science.gov (United States)

    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. Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress.

    Science.gov (United States)

    Friederich-Persson, Malou; Thörn, Erik; Hansell, Peter; Nangaku, Masaomi; Levin, Max; Palm, Fredrik

    2013-11-01

    Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

  6. Periods of cardiovascular susceptibility to hypoxia in embryonic american alligators (Alligator mississippiensis).

    Science.gov (United States)

    Tate, Kevin B; Rhen, Turk; Eme, John; Kohl, Zachary F; Crossley, Janna; Elsey, Ruth M; Crossley, Dane A

    2016-06-01

    During embryonic development, environmental perturbations can affect organisms' developing phenotype, a process known as developmental plasticity. Resulting phenotypic changes can occur during discrete, critical windows of development. Critical windows are periods when developing embryos are most susceptible to these perturbations. We have previously documented that hypoxia reduces embryo size and increases relative heart mass in American alligator, and this study identified critical windows when hypoxia altered morphological, cardiovascular function and cardiac gene expression of alligator embryos. We hypothesized that incubation in hypoxia (10% O2) would increase relative cardiac size due to cardiac enlargement rather than suppression of somatic growth. We exposed alligator embryos to hypoxia during discrete incubation periods to target windows where the embryonic phenotype is altered. Hypoxia affected heart growth between 20 and 40% of embryonic incubation, whereas somatic growth was affected between 70 and 90% of incubation. Arterial pressure was depressed by hypoxic exposure during 50-70% of incubation, whereas heart rate was depressed in embryos exposed to hypoxia during a period spanning 70-90% of incubation. Expression of Vegf and PdgfB was increased in certain hypoxia-exposed embryo treatment groups, and hypoxia toward the end of incubation altered β-adrenergic tone for arterial pressure and heart rate. It is well known that hypoxia exposure can alter embryonic development, and in the present study, we have identified brief, discrete windows that alter the morphology, cardiovascular physiology, and gene expression in embryonic American alligator.

  7. [Effects of exogenous spermidine on Cucumis sativus L. seedlings photosynthesis under root zone hypoxia stress].

    Science.gov (United States)

    Wang, Tian; Wang, Suping; Guo, Shirong; Sun, Yanjun

    2006-09-01

    With water culture, this paper studied the effects of exogenous spermidine (Spd) on the net photosynthetic rate (Pn), intercellular CO2 concentrations (Ci), stomatal conductance (Gs), transpiration rate (Tr), apparent quantum yield (phi c), and carboxylation efficiency (CE) of cucumber seedlings tinder hypoxia stress. The results showed that the Pn decreased gradually under hypoxia stress, and reached the minimum 10 days after by 63. 33% of the control. Compared with that of hypoxia-stressed plants, the Pn after 10 days application of exogenous Spd increased 1.25 times. A negative correlation (R2 = 0.4730 - 0.7118) was found between Pn and Ci. Gs and Tr changed in wider ranges, which decreased under hypoxia-stress, but increased under hypoxia-stress plus exogenous Spd application. There was a significant positive correlation between Gs and Tr (R2 = 0.7821 - 0.9458), but these two parameters had no significant correlation with Pn; Hypoxia stress induced a decrease of phi c and CE by 63.01% and 72.33%, respectively, while hypoxia stress plus exogenous Spd application made phi c and CE increase by 23% and 14%, respectively. The photo-inhibition of cucumber seedlings under hypoxia stress was mainly caused by non-stomatal limitation, while exogenous Spd alleviated the hypoxia stress by repairing photosynthesis system.

  8. Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.

    LENUS (Irish Health Repository)

    Biniecka, Monika

    2012-02-01

    OBJECTIVE: To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels. METHODS: Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2\\'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups. RESULTS: The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC. CONCLUSION: These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives

  9. Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo

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    Vassiliki Kostourou

    2004-07-01

    Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

  10. Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells.

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    Aiping Lan

    Full Text Available Hydrogen sulfide (H(2S has been proposed as a novel neuromodulator and neuroprotective agent. Cobalt chloride (CoCl(2 is a well-known hypoxia mimetic agent. We have demonstrated that H(2S protects against CoCl(2-induced injuries in PC12 cells. However, whether the members of mitogen-activated protein kinases (MAPK, in particular, extracellular signal-regulated kinase1/2(ERK1/2 and p38MAPK are involved in the neuroprotection of H(2S against chemical hypoxia-induced injuries of PC12 cells is not understood. We observed that CoCl(2 induced expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α, decreased cystathionine-β synthase (CBS, a synthase of H(2S expression, and increased generation of reactive oxygen species (ROS, leading to injuries of the cells, evidenced by decrease in cell viability, dissipation of mitochondrial membrane potential (MMP , caspase-3 activation and apoptosis, which were attenuated by pretreatment with NaHS (a donor of H(2S or N-acetyl-L cystein (NAC, a ROS scavenger. CoCl(2 rapidly activated ERK1/2, p38MAPK and C-Jun N-terminal kinase (JNK. Inhibition of ERK1/2 or p38MAPK or JNK with kinase inhibitors (U0126 or SB203580 or SP600125, respectively or genetic silencing of ERK1/2 or p38MAPK by RNAi (Si-ERK1/2 or Si-p38MAPK significantly prevented CoCl(2-induced injuries. Pretreatment with NaHS or NAC inhibited not only CoCl(2-induced ROS production, but also phosphorylation of ERK1/2 and p38MAPK. Thus, we demonstrated that a concurrent activation of ERK1/2, p38MAPK and JNK participates in CoCl(2-induced injuries and that H(2S protects PC12 cells against chemical hypoxia-induced injuries by inhibition of ROS-activated ERK1/2 and p38MAPK pathways. Our results suggest that inhibitors of ERK1/2, p38MAPK and JNK or antioxidants may be useful for preventing and treating hypoxia-induced neuronal injury.

  11. Ang Ⅱ type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia: effects of p38MAPK and ERK1/2 signaling

    Institute of Scientific and Technical Information of China (English)

    SHANG Jin; YANG Yuan-yuan; GUO Xue-ling; LIU Hui-guo

    2013-01-01

    Background Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension.Ang Ⅱ type 1 receptor (AT1R) played important roles in hypertension since it binds with Ang Ⅱ,controlling salt-water and blood pressure homeostasis.This study explores rat aorta AT1R expression during intermittent hypoxia (IH) and the signaling pathways involved.Methods A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively.The arterial blood pressure was recorded by a Nihon Kohden Polygraph System.Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta.Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression.Results In this study,we found that chronic intermittent hypoxia (CIH) induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia.The AT1R protein expression in the aorta was similar to the real-time PCR results.We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting.Compared to normoxia,CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia (SH) upregulated ERK2 but not ERK1 or p38MAPK mRNA.In cells,IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation,whereas SH induced only ERK1/2 phosphorylation.The ERK1/2 inhibitor PD98059 attenuated the IHinduced AT1R increase but the p38MAPK inhibitor SB203580 did not.Conclusions Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression.Moreover,AT1R expression in IH and sustained hypoxia might be regulated by different signal transduction pathways,highlighting a novel regulatory function through ERK1/2 signaling in IH.

  12. Hypoxia-induced cell death and changes in hypoxia-inducible factor-1 activity in PC12 cells upon exposure to nerve growth factor.

    Science.gov (United States)

    Charlier, Nico; Leclere, Norbert; Felderhoff, Ursula; Heldt, Julia; Kietzmann, Thomas; Obladen, Michael; Gross, Johann

    2002-07-15

    The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (Annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes responsible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierarchically organized signaling molecule.

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

    Directory of Open Access Journals (Sweden)

    Mahendran Botlagunta

    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.

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

    Science.gov (United States)

    Botlagunta, Mahendran; Krishnamachary, Balaji; Vesuna, Farhad; Winnard, Paul T; Bol, Guus M; Patel, Arvind H; Raman, Venu

    2011-03-23

    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.

  15. Acute hypoxia up-regulates HIF-1α and VEGF mRNA levels in Amazon hypoxia-tolerant Oscar (Astronotus ocellatus).

    Science.gov (United States)

    Baptista, R B; Souza-Castro, N; Almeida-Val, V M F

    2016-10-01

    Amazon fish maintain oxygen uptake through a variety of strategies considered evolutionary and adaptive responses to the low water oxygen saturation, commonly found in Amazon waters. Oscar (Astronotus ocellatus) is among the most hypoxia-tolerant fish in Amazon, considering its intriguing anaerobic capacity and ability to depress oxidative metabolism. Previous studies in hypoxia-tolerant and non-tolerant fish have shown that hypoxia-inducible factor-1α (HIF-1α) gene expression is positively regulated during low oxygen exposure, affecting vascular endothelial growth factor (VEGF) transcription and fish development or tolerance in different manners. However, whether similar isoforms exists in tolerant Amazon fish and whether they are affected similarly to others physiological responses to improve hypoxia tolerance remain unknown. Here we evaluate the hepatic HIF-1α and VEGF mRNA levels after 3 h of acute hypoxia exposure (0.5 mgO2/l) and 3 h of post-hypoxia recovery. Additionally, hematological parameters and oxidative enzyme activities of citrate synthase (CS) and malate dehydrogenase (MDH) were analyzed in muscle and liver tissues. Overall, three sets of responses were detected: (1) as expected, hematocrit, hemoglobin concentration, red blood cells, and blood glucose increased, improving oxygen carrying capacity and glycolysis potential; (2) oxidative enzymes from liver decreased, corroborating the tendency to a widespread metabolic suppression; and (3) HIF-1α and VEGF increased mRNA levels in liver, revealing their role in the oxygen homeostasis through, respectively, activation of target genes and vascularization. This is the first study to investigate a hypoxia-related transcription factor in a representative Amazon hypoxia-tolerant fish and suggests that HIF-1α and VEGF mRNA regulation have an important role in enhancing hypoxia tolerance in extreme tolerant species.

  16. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

    Science.gov (United States)

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

  17. Hypothermia reduces VEGF-165 expression, but not osteogenic differentiation of human adipose stem cells under hypoxia

    Science.gov (United States)

    Bakker, Astrid D.; Hogervorst, Jolanda M. A.; Nolte, Peter A.; Klein-Nulend, Jenneke

    2017-01-01

    Cryotherapy is successfully used in the clinic to reduce pain and inflammation after musculoskeletal damage, and might prevent secondary tissue damage under the prevalent hypoxic conditions. Whether cryotherapy reduces mesenchymal stem cell (MSC) number and differentiation under hypoxic conditions, causing impaired callus formation is unknown. We aimed to determine whether hypothermia modulates proliferation, apoptosis, nitric oxide production, VEGF gene and protein expression, and osteogenic/chondrogenic differentiation of human MSCs under hypoxia. Human adipose MSCs were cultured under hypoxia (37°C, 1% O2), hypothermia and hypoxia (30°C, 1% O2), or control conditions (37°C, 20% O2). Total DNA, protein, nitric oxide production, alkaline phosphatase activity, gene expression, and VEGF protein concentration were measured up to day 8. Hypoxia enhanced KI67 expression at day 4. The combination of hypothermia and hypoxia further enhanced KI67 gene expression compared to hypoxia alone, but was unable to prevent the 1.2-fold reduction in DNA amount caused by hypoxia at day 4. Addition of hypothermia to hypoxic cells did not alter the effect of hypoxia alone on BAX-to-BCL-2 ratio, alkaline phosphatase activity, gene expression of SOX9, COL1, or osteocalcin, or nitric oxide production. Hypothermia decreased the stimulating effect of hypoxia on VEGF-165 gene expression by 6-fold at day 4 and by 2-fold at day 8. Hypothermia also decreased VEGF protein expression under hypoxia by 2.9-fold at day 8. In conclusion, hypothermia decreased VEGF-165 gene and protein expression, but did not affect differentiation, or apoptosis of MSCs cultured under hypoxia. These in vitro results implicate that hypothermia treatment in vivo, applied to alleviate pain and inflammation, is not likely to harm early stages of callus formation. PMID:28166273

  18. 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

  19. Imaging Rayleigh wave attenuation with USArray

    Science.gov (United States)

    Bao, Xueyang; Dalton, Colleen A.; Jin, Ge; Gaherty, James B.; Shen, Yang

    2016-07-01

    The EarthScope USArray provides an opportunity to obtain detailed images of the continental upper mantle at an unprecedented scale. The majority of mantle models derived from USArray data to date contain spatial variations in seismic-wave speed; however, in many cases these data sets do not by themselves allow a non-unique interpretation. Joint interpretation of seismic attenuation and velocity models can improve upon the interpretations based only on velocity and provide important constraints on the temperature, composition, melt content, and volatile content of the mantle. The surface wave amplitudes that constrain upper-mantle attenuation are sensitive to factors in addition to attenuation, including the earthquake source excitation, focusing and defocusing by elastic structure, and local site amplification. Because of the difficulty of isolating attenuation from these other factors, little is known about the attenuation structure of the North American upper mantle. In this study, Rayleigh wave traveltime and amplitude in the period range 25-100 s are measured using an interstation cross-correlation technique, which takes advantage of waveform similarity at nearby stations. Several estimates of Rayleigh wave attenuation and site amplification are generated at each period, using different approaches to separate the effects of attenuation and local site amplification on amplitude. It is assumed that focusing and defocusing effects can be described by the Laplacian of the traveltime field. All approaches identify the same large-scale patterns in attenuation, including areas where the attenuation values are likely contaminated by unmodelled focusing and defocusing effects. Regionally averaged attenuation maps are constructed after removal of the contaminated attenuation values, and the variations in intrinsic shear attenuation that are suggested by these Rayleigh wave attenuation maps are explored.

  20. Protection of neuroblastoma Neuro2A cells from hypoxia-induced apoptosis by cyclic phosphatidic acid (cPA.

    Directory of Open Access Journals (Sweden)

    Mari Gotoh

    Full Text Available Cyclic phosphatidic acid (cPA is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We have previously shown that cPA significantly suppresses ischemia-induced delayed neuronal death and the accumulation of glial fibrillary acidic protein in the CA1 region of the rat hippocampus. These results indicated that the systemic administration of cPA can protect hippocampal neurons against ischemia-induced delayed neuronal cell death. In the current study, we investigated the effects of cPA on neuronal cell death caused by hypoxia in vitro and the molecular mechanisms underlying these effects. We used cobalt chloride (CoCl(2 to expose cells to hypoxic conditions in vitro. Treating mouse neuroblastoma (Neuro2A cells with CoCl(2 induced nuclear DNA condensation and phosphatidylserine exposure. However, adding cPA led to the suppression of CoCl(2-induced apoptosis in a cPA dose-dependent manner and attenuated the increase in the Bax/Bcl-2 ratio caused by CoCl(2. Quantitative PCR analysis showed that Neuro2A cells strongly express the LPA(1, LPA(2, and LPA(6, which are G-protein coupled receptors that can be activated by cPA. To date, LPA(1 and LPA(2 have been reported to exhibit antiapoptotic activity. Therefore, to assess the roles of LPA(1 and LPA(2 on cPA-induced neuroprotective functions, Ki16425, a selective LPA(1 and LPA(3 antagonist, was adopted to know the LPA(1 function and siRNA was used to knockdown the expression of LPA(2. On the basis of our results, we propose that cPA-induced protection of Neuro2A cells from CoCl(2-induced hypoxia damage is mediated via LPA(2.

  1. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

    Directory of Open Access Journals (Sweden)

    S.D. Chai

    2016-01-01

    Full Text Available Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH rat model. Sprague Dawley rats (n=40 were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP and the right ventricle (RV to left ventricle plus the interventricular septum (LV+S mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA, TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling.

  2. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes

    OpenAIRE

    Mojsilovic-Petrovic Jelena; Callaghan Debbie; Cui Hong; Dean Clare; Stanimirovic Danica B; Zhang Wandong

    2007-01-01

    Abstract Background Neuroinflammation has been implicated in various brain pathologies characterized by hypoxia and ischemia. Astroglia play an important role in the initiation and propagation of hypoxia/ischemia-induced inflammation by secreting inflammatory chemokines that attract neutrophils and monocytes into the brain. However, triggers of chemokine up-regulation by hypoxia/ischemia in these cells are poorly understood. Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional fact...

  3. TGFβ and Hypoxia Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

    Institute of Scientific and Technical Information of China (English)

    Lauren K. DUNN; Pierrick G.J. FOURNIE; Khalid S. MOHAMMAD; C. Ryan MCKENNA; Holly W. DAVIS; Maria NIEWOLNA; Xianghong PENG; John M. CHIRGWIN; Theresa A.GUISE

    2009-01-01

    @@ Breast cancers frequently metastasize to bone, a site of hypoxia and high concentrations of active TGFβ. Skeletal metastases involve interactions between tumor and bone cells driven by locally secreted proteins, many of which are increased by hypoxia and TGFβ.

  4. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    Energy Technology Data Exchange (ETDEWEB)

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-12-01

    We have developed and tested technology for a new type of direct hydrocarbon detection. The method uses inelastic rock properties to greatly enhance the sensitivity of surface seismic methods to the presence of oil and gas saturation. These methods include use of energy absorption, dispersion, and attenuation (Q) along with traditional seismic attributes like velocity, impedance, and AVO. Our approach is to combine three elements: (1) a synthesis of the latest rock physics understanding of how rock inelasticity is related to rock type, pore fluid types, and pore microstructure, (2) synthetic seismic modeling that will help identify the relative contributions of scattering and intrinsic inelasticity to apparent Q attributes, and (3) robust algorithms that extract relative wave attenuation attributes from seismic data. This project provides: (1) Additional petrophysical insight from acquired data; (2) Increased understanding of rock and fluid properties; (3) New techniques to measure reservoir properties that are not currently available; and (4) Provide tools to more accurately describe the reservoir and predict oil location and volumes. These methodologies will improve the industry's ability to predict and quantify oil and gas saturation distribution, and to apply this information through geologic models to enhance reservoir simulation. We have applied for two separate patents relating to work that was completed as part of this project.

  5. Magnetoelectric Composite Based Microwave Attenuator

    Science.gov (United States)

    Tatarenko, A. S.; Srinivasan, G.

    2005-03-01

    Ferrite-ferroelectric composites are magnetoelectric (ME) due to their response to elastic and electromagnetic force fields. The ME composites are characterized by tensor permittivity, permeability and ME susceptibility. The unique combination of magnetic, electrical, and ME interactions, therefore, opens up the possibility of electric field tunable ferromagnetic resonance (FMR) based devices [1]. Here we discuss an ME attenuator operating at 9.3 GHz based on FMR in a layered sample consisting of lead magnesium niobate-lead titanate bonded to yttrium iron garnet (YIG) film on a gadolinium gallium garnet substrate. Electrical tuning is realized with the application of a control voltage due to ME effect; the shift is 0-15 Oe as E is increased from 0 to 3 kV/cm. If the attenuator is operated at FMR, the corresponding insertion loss will range from 25 dB to 2 dB. 1. S. Shastry and G. Srinivasan, M.I. Bichurin, V.M. Petrov, A.S. Tatarenko. Phys. Rev. B, 70 064416 (2004). - supported by grants the grants from the National Science Foundation (DMR-0302254), from Russian Ministry of Education (Å02-3.4-278) and from Universities of Russia Foundation (UNR 01.01.026).

  6. Attenuation map reconstruction from TOF PET data

    CERN Document Server

    Yang, Qingsong; Wang, Ge

    2013-01-01

    To reconstruct a radioactive tracer distribution with positron emission tomography (PET), the background attenuation correction is needed to eliminate image artifacts. Recent research shows that time-of-flight (TOF) PET data determine the attenuation sinogram up to a constant, and its gradient can be computed using an analytic algorithm. In this paper, we study a direct estimation of the sinogram only from TOF PET data. First, the gradient of the attenuation sinogram is estimated using the aforementioned algorithm. Then, a relationship is established to link the differential attenuation sinogram and the underlying attenuation background. Finally, an iterative algorithm is designed to determine the attenuation sinogram accurately and stably. A 2D numerical simulation study is conducted to verify the correctness of our proposed approach.

  7. Acute hypoxia and cytochrome P450-mediated hepatic drug metabolism in humans

    DEFF Research Database (Denmark)

    Jürgens, Gesche; Christensen, Hanne Rolighed; Brøsen, Kim;

    2002-01-01

    Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.......Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes....

  8. Cardiac and plasma lipid profiles in response to acute hypoxia in neonatal and young adult rats

    Directory of Open Access Journals (Sweden)

    Raff Hershel

    2010-01-01

    Full Text Available Abstract Background The physiological and biochemical responses to acute hypoxia have not been fully characterized in neonates. Fatty acids and lipids play an important role in most aspects of cardiac function. Methods We performed comprehensive lipid profiling analysis to survey the changes that occur in heart tissue and plasma of neonatal and young adult rats exposed to hypoxia for 2 h, and following 2 h of recovery from hypoxia. Results Cardiac and plasma concentrations of short-chain acylcarnitines, and most plasma long-chain fatty acids, were decreased in hypoxic neonates. Following recovery from hypoxia, concentrations of propionylcarnitine, palmitoylcarnitine, stearoylcarnitine were increased in neonatal hearts, while oleylcarnitine and linoleylcarnitine concentrations were increased in neonatal plasma. The concentrations of long-chain fatty acids and long-chain acylcarnitines were increased in the hearts and plasma of hypoxic young adult rats; these metabolites returned to baseline values following recovery from hypoxia. Conclusion There are differential effects of acute hypoxia on cardiac and plasma lipid profiles with maturation from the neonate to the young adult rat. Changes to neonatal cardiac and plasma lipid profiles during hypoxia likely allowed for greater metabolic and physiologic flexibility and increased chances for survival. Persistent alterations in the neonatal cardiac lipid profile following recovery from hypoxia may play a role in the development of rhythm disturbances.

  9. Hypoxia and HIFs in regulating the development of the hematopoietic system

    NARCIS (Netherlands)

    P. Imanirad (Parisa); E.A. Dzierzak (Elaine)

    2013-01-01

    textabstractMany physiologic processes during the early stages of mammalian ontogeny, particularly placental and vascular development, take place in the low oxygen environment of the uterus. Organogenesis is affected by hypoxia inducible factor (HIF) transcription factors that are sensors of hypoxia

  10. The effect of hypoxia on shortening contractions in rat diaphragm muscle.

    NARCIS (Netherlands)

    Machiels, H.A.; Heijden, E. van der; Heunks, L.M.A.; Dekhuijzen, P.N.R.

    2001-01-01

    Hypoxia is known to reduce isometric contractile properties of isolated rat diaphragm bundles. Its effect on isotonic contractile properties (i.e. force-velocity relationship and power output) has not been studied. We hypothesized that hypoxia reduces velocity of shortening and consequently power ou

  11. Hypoxia-induced mobilization of stored triglycerides in the euryoxic goby Gillichthys mirabilis.

    Science.gov (United States)

    Gracey, Andrew Y; Lee, Tsung-Han; Higashi, Richard M; Fan, Teresa

    2011-09-15

    Environmental hypoxia is a common challenge that many aquatic organisms experience in their habitat. Responding to hypoxia requires metabolic reprogramming so that energy-demanding processes are regulated to match available energy reserves. In this study we explored the transcriptional control of metabolic reorganization in the liver of a hypoxia-tolerant burrow-dwelling goby, Gillichthys mirabilis. Gene expression data revealed that pathways associated with triglyceride hydrolysis were upregulated by hypoxia whereas pathways associated with triglyceride synthesis were downregulated. This finding was supported by tissue histology, which showed that the size of hepatic lipid droplets declined visibly during exposure to hypoxia. Proton nuclear magnetic resonance analysis confirmed the mobilization of hepatic triglycerides, which declined 2.7-fold after 5 days of hypoxia. The enzyme, adipose triglyceride lipase, was implicated in the mobilization of triglycerides because its expression increased at the level of both transcript and protein. This observation raises questions regarding the regulation of fat metabolism during hypoxia and the role played by the hypoxia-responsive gene leptin.

  12. [The answer reaction of system complement on correction of hypoxia of hydazepam and succinic acid].

    Science.gov (United States)

    Kuznetsova, L N

    2011-01-01

    Investigated functionally activation of human complement in vivo an model of high hypoxia (6-7,5 km) as without correction, so at the phone of medicine hydazepam and succinic acid. Discover that by analysis of the sensitive to complement components one can estimate effects of high hypoxia and her pharmacological correction.

  13. Contrasting effects of ascorbate and iron on the pulmonary vascular response to hypoxia in humans.

    Science.gov (United States)

    Talbot, Nick P; Croft, Quentin P; Curtis, M Kate; Turner, Brandon E; Dorrington, Keith L; Robbins, Peter A; Smith, Thomas G

    2014-12-01

    Hypoxia causes an increase in pulmonary artery pressure. Gene expression controlled by the hypoxia-inducible factor (HIF) family of transcription factors plays an important role in the underlying pulmonary vascular responses. The hydroxylase enzymes that regulate HIF are highly sensitive to varying iron availability, and iron status modifies the pulmonary vascular response to hypoxia, possibly through its effects on HIF. Ascorbate (vitamin C) affects HIF hydroxylation in a similar manner to iron and may therefore have similar pulmonary effects. This study investigated the possible contribution of ascorbate availability to hypoxic pulmonary vasoconstriction in humans. Seven healthy volunteers undertook a randomized, controlled, double-blind, crossover protocol which studied the effects of high-dose intravenous ascorbic acid (total 6 g) on the pulmonary vascular response to 5 h of sustained hypoxia. Systolic pulmonary artery pressure (SPAP) was assessed during hypoxia by Doppler echocardiography. Results were compared with corresponding data from a similar study investigating the effect of intravenous iron, in which SPAP was measured in seven healthy volunteers during 8 h of sustained hypoxia. Consistent with other studies, iron supplementation profoundly inhibited hypoxic pulmonary vasoconstriction (P ascorbate did not affect the increase in pulmonary artery pressure induced by several hours of hypoxia (P = 0.61). We conclude that ascorbate does not interact with hypoxia and the pulmonary circulation in the same manner as iron. Whether the effects of iron are HIF-mediated remains unknown, and the extent to which ascorbate contributes to HIF hydroxylation in vivo is also unclear.

  14. Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion.

    Science.gov (United States)

    Hoang, Mien V; Smith, Lois E H; Senger, Donald R

    2011-04-01

    In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

  15. Natural and human-induced hypoxia and consequences for coastal areas: synthesis and future development

    NARCIS (Netherlands)

    Zhang, J.Z.; Gilbert, D.; Gooday, A.J.; Levin, L.A.; Naqvi, S.W.A.; Middelburg, J.J.; Scranton, M.; Ekau, W.; Pena, A.; Dewitte, B.; Oguz, T.; Monteiro, P.M.S.; Urban, E.; Rabalais, N.; Ittekkot, V.; Kemp, W.M.; Ulloa, O.; Elmgren, R.; Escobar-Briones, E.; Van der Plas, A.K.

    2010-01-01

    Hypoxia has become a world-wide phenomenon in the global coastal ocean and causes a deterioration of the structure and function of ecosystems. Based on the collective contributions of members of SCOR Working Group #128, the present study provides an overview of the major aspects of coastal hypoxia i

  16. Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress.

    Directory of Open Access Journals (Sweden)

    Daliao Xiao

    Full Text Available Chronic hypoxia during gestation has profound adverse effects on the adaptation of uteroplacental circulation in pregnancy. Yet, the underlying mechanisms are not fully understood. The present study tested the hypothesis that enhanced production of reactive oxygen species (ROS in uterine arteries plays a critical role in the maladaptation of uterine circulation associated with chronic hypoxia. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep maintained at sea level (~300 m or exposed to high-altitude (3801 m hypoxia for 110 days. Hypoxia significantly increased ROS production in uterine arteries of pregnant, but not nonpregnant, sheep. This was associated with a significant increase in NADPH oxidase (Nox 2, but not Nox1 or Nox4, protein abundance and total Nox activity in uterine arteries of pregnant animals. Chronic hypoxia significantly increased pressure-dependent uterine arterial myogenic tone in pregnant sheep, which was abrogated by a Nox inhibitor apocynin. Additionally, the hypoxia-induced increase in myogenic reactivity of uterine arteries to phorbol 12,13-dibutyrate in pregnant sheep was blocked by apocynin and tempol. In consistence with the myogenic responses, the hypoxia-mediated down-regulation of BKCa channel activity in uterine arteries of pregnant animals was reversed by apocynin. The findings suggest that heightened oxidative stress in uterine arteries plays a key role in suppressing the BKCa channel activity, resulting in increased myogenic reactivity and maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation.

  17. Effects of exogenous spermidine on the photosynthesis of Cucumis sativus L. seedlings under rhizosphere hypoxia stress

    Institute of Scientific and Technical Information of China (English)

    Tian WANG; Suping WANG; Shirong GUO; Yanjun SUN

    2008-01-01

    With water culture, this paper studied the effects of exogenous spermidine (Spd) on the net photosynthetic rate (Pn),intercellular CO2 concentra-tions (Ci),stomatal conductance(Gs),transpiration rate efficiency (CE) of cucumber seedlings under hypoxia stress. The results showed that Pn decreased gradually under the hypoxia stress, and reached the minimum 10 days later, which was 63.33% of the control. Compared with that of the hypoxia-stressed plants, the Pn 10 days after the application of exogenous Spd increased by 1.25 times. A negative correlation (R2=0.473-0.7118) was found between Pn and Ci, and Gs and Tr changed in wider ranges, which decreased under the hypoxia-stress, but increased under the hypoxia-stress plus exogenous Spd application. There was a significant positive correlation between Gs and Tr (R2=0.7821-0.9458), but these two parameters had no significant correlation with Pn. The 63.01% and 72.33%, respectively, while the hypoxia stress by 23% and 14%, respectively. The photo-inhibition of cucumber seedlings under hypoxia stress was mainly caused by non-stomatal inhibition, while the exogenous Spd alleviating the hypoxia stress by repairing photosyn-thesis systems.

  18. Hypoxia diminishes the detoxification of the environmental mutagen benzo[a]pyrene

    NARCIS (Netherlands)

    Schults, Marten A.; Sanen, Kathleen; Godschalk, Roger W.; Theys, Jan; van Schooten, Frederik J.; Chiu, Roland K.

    2014-01-01

    Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIF alpha can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elu

  19. FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

    DEFF Research Database (Denmark)

    Jensen, Kim Steen; Binderup, Tina; Jensen, Klaus Thorleif

    2011-01-01

    Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful...

  20. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

    DEFF Research Database (Denmark)

    Siebenmann, Christoph; Rasmussen, Peter; Sørensen, Henrik;

    2015-01-01

    Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exerci...

  1. Hypoxia and Nutrient Reduction in the Coastal Zone: Advice for Prevention, Remediation and Research.

    Digital Repository Service at National Institute of Oceanography (India)

    Meryl Williams, M.; Harper, N.; Chaitovitz, C.; Dansie, A.; Diaz, R.; Harper, N.; Heidemeier, J.; Jiang, Y.; Kemp, M.; Naqvi, S.W.A.; Neretin, L.; Ross, A.; Susan, C.; Schuster-Wallace, C.; Zavadksy, I.

    of Mexico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Guinea Current . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Chesapeake Bay (non-GEF case... database, GEF LME project references to hypoxia were compared with those in the global scientific hypoxia database of Prof. R. Diaz. 3 For six LMEs (Gulf of Mexico, Mediterranean Sea, Black Sea, Guinea Current, Red Sea and Yellow Sea), GEF project...

  2. Hypoxia-inducible factors - regulation, role and comparative aspects in tumourigenesis

    DEFF Research Database (Denmark)

    Hansen, A E; Kristensen, A T; Law, I;

    2011-01-01

    Hypoxia-inducible factors (HIFs) play a key role in the cellular response experienced in hypoxic tumours, mediating adaptive responses that allow hypoxic cells to survive in the hostile environment. Identification and understanding of tumour hypoxia and the influence on cellular processes carries...

  3. Preventive effect of piracetam and vinpocetine on hypoxia-reoxygenation induced injury in primary hippocampal culture.

    Science.gov (United States)

    Solanki, P; Prasad, D; Muthuraju, S; Sharma, A K; Singh, S B; Ilavzhagan, G

    2011-04-01

    The present study investigates the potential of Piracetam and Vinpocetine (nootropic drugs, known to possess neuroprotective properties) in preventing hypoxia-reoxygenation induced oxidative stress in primary hippocampal cell culture. The hippocampal culture was exposed to hypoxia (95% N(2), 5% CO(2)) for 3h and followed by 1h of reoxygenation (21% O(2) and 5% CO(2)) at 37 °C. The primary hippocampal cultures were supplemented with the optimum dose of Piracetam and Vinpocetine, independently, and the cultures were divided into six groups, viz. Control/Normoxia, Hypoxia, Hypoxia+Piracetam, Hypoxia+Vinpocetine, Normoxia + Piracetam and Normoxia+Vinpocetine. The cell-viability assays and biochemical oxidative stress parameters were evaluated for each of the six groups. Administration of 1mM Piracetam or 500 nM Vinpocetine significantly prevents the culture from hypoxia-reoxygenation injury when determined by Neutral Red assay, LDH release and Acetylcholine esterase activity. Results showed that Piracetam and Vinpocetine supplementation significantly prevented the fall of mitochondrial membrane potential, rise in ROS generation and reduction in antioxidant levels associated with the hypoxia-reoxygenation injury. In conclusion, the present study establishes that both Piracetam and Vinpocetine give neuroprotection against hypoxia-reoxygenation injury in primary hippocampal cell culture.

  4. Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI

    Science.gov (United States)

    2011-10-01

    performed in rats with/without cervical injuries : 1) shelf controls; 2) sham; 3) daily treadmill training for five days; 4) intermittent hypoxia for...combining our results with parallel behavioral studies. 15. SUBJECT TERMS Spinal Injury , Treatment , Intermittent hypoxia, humans, rats, BDNF 16...the translational partnership award is to assess changes in ventral spinal protein expression in rats with cervical spinal injuries following

  5. A rat pup model of cerebral palsy induced by prenatal inflammation and hypoxia

    Institute of Scientific and Technical Information of China (English)

    Yanrong Hu; Feng Gao; Jianxin Li; Lihui Zhao; Gang Chen; Hong Wan; Zhiyou Zhang; Hong Zhi; Wei Liu; Xinwei Qian; Mingzhao Chen; Linbao Wen

    2013-01-01

    Animal models of cerebral palsy established by simple infection or the hypoxia/ischemia method cannot effectively simulate the brain injury of a premature infant. Healthy 17-day-pregnant Wistar rats were intraperitoneally injected with lipopolysaccharide then subjected to hypoxia. The pups were used for this study at 4 weeks of age. Simultaneously, a hypoxia/ischemia group and a control group were used for comparison. The results of the footprint test, the balance beam test, the water maze test, neuroelectrophysiological examination and neuropathological examination demonstrated that, at 4 weeks after birth, footprint repeat space became larger between the forelimbs and hindlimbs of the rats, the latency period on the balance beam and in the Morris water maze was longer, place navigation and ability were poorer, and the stimulus intensity that induced the maximal wave amplitude of the compound muscle action potential was greater in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups than in the control group. We observed irregular cells around the periventricular area, periventricular leukomalacia and breakage of the nuclear membrane in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups. These results indicate that we successfully established a Wistar rat pup model of cerebral palsy by intraperitoneal injection of lipopolysaccharide and hypoxia.

  6. Hypoxia: A Master Regulator of MicroRNA Biogenesis and Activity

    Science.gov (United States)

    Nallamshetty, Shriram; Chan, Stephen Y.; Loscalzo, Joseph

    2013-01-01

    Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins in order to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short non-coding RNAs that regulate gene expression through post-transcriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor (HIF) are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated order to integrate into the complex hierarchical regulatory network induced by hypoxia. PMID:23712003

  7. Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia.

    Directory of Open Access Journals (Sweden)

    Gaoliang Yan

    Full Text Available AIMS: Arachidonic acid (AA and its metabolites, prostaglandins (PG are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs. METHODS AND RESULTS: We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM, an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV. CONCLUSION: Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca(2+ channels.

  8. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis

    Science.gov (United States)

    Gupta, Ram; Chaudhary, Anita R; Shah, Binita N; Jadhav, Avinash V; Zambad, Shitalkumar P; Gupta, Ramesh Chandra; Deshpande, Shailesh; Chauthaiwale, Vijay; Dutt, Chaitanya

    2014-01-01

    Background and aim Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn’s disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD. PMID:24493931

  9. ERK signaling mediates enhanced angiotensin Ⅱ-induced rat aortic constriction following chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    GUO Xue-ling; DENG Yan; SHANG Jin; LIU Kui; XU Yong-jian; LIU Hui-guo

    2013-01-01

    Background Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for systemic hypertension.The study investigated the functional consequences of chronic intermittent hypoxia (CIH) on aortic constriction induced by angiotensin Ⅱ (Ang Ⅱ) and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase (MLCK),myosin phosphatase targeting subunit (MYPT1) and myosin light chain (MLC).Methods Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles.Phosphorylation of ERK1/2,MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 (10 μmol/L).Results CIH-exposure resulted in more body weight gain and elevated blood pressure,which could be attenuated by pretreatment with PD98059.Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang Ⅱ (Emax:(138.56±5.78)% versus (98.45±5.31)% of KCI; pD2:7.98±0.14 versus 8.14±0.05,respectively).CIH procedure exerted complex effects on ERK expressions (total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2increased).CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC.In parallel to greater increases in phosphorylation of ERK1/2,MYPT1 and MLC,Ang Ⅱ-induced aortic constriction was significantly enhanced in CIH rats,which was largely reversed by PD98059.However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation.Conclusion These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang Ⅱ,presumably owing to more activated ERK1/2 signaling pathway.

  10. Chronic overexpression of cerebral Epo improves the ventilatory response to acute hypoxia during the postnatal development.

    Science.gov (United States)

    Caravagna, Céline; Gasser, Edith M Schneider; Ballot, Orlane; Joseph, Vincent; Soliz, Jorge

    2015-08-01

    Clinicians observed that the treatment of premature human newborns for anemia with erythropoietin (Epo) also improved their respiratory autonomy. This observation is in line with our previous in vitro studies showing that acute and chronic Epo stimulation enhances fictive breathing of brainstem-spinal cord preparations of postnatal day 3-4 mice during hypoxia. Furthermore, we recently reported that the antagonization of the cerebral Epo (by using the soluble Epo receptor; sEpoR) significantly reduced the basal ventilation and the hypoxic ventilatory response of 10 days old mice. In this study, we used transgenic (Tg21) mice to investigate the effect of the chronic cerebral Epo overexpression on the modulation of the normoxic and hypoxic ventilatory drive during the post-natal development. Ventilation was evaluated by whole body plethysmography at postnatal ages 3 (P3), 7 (P7), 15 (P15) and 21 (P21). In addition Epo quantification was performed by RIA and mRNA EpoR was evaluated by qRT-PCR. Our results showed that compared to control animals the chronic Epo overexpression stimulates the hypoxic (but not the normoxic) ventilation assessed as VE/VO2 at the ages of P3 and P21. More interestingly, we observed that at P7 and P15 the chronic Epo stimulation of ventilation was attenuated by the down regulation of the Epo receptor in brainstem areas. We conclude that Epo, by stimulating ventilation in brainstem areas crucially helps tolerating physiological (e.g., high altitude) and/or pathological (e.g., respiratory disorders, prematurity, etc.) oxygen deprivation at postnatal ages.

  11. Effect of Fasting on Tolerance to Moderate Hypoxia,

    Science.gov (United States)

    Blood pressure response to moderate hypoxia was compared in a fasting and a control (non- fasting ) state in 10 seated subjects. End-tidal gas tensions...exposure to a simulated altitude of 17,000 ft. When exposed to the same stress after fasting for 18 hours, the MAP fell to 87% (P less than 0.01) of...its resting value. The mean end-tidal Po2 was significantly lower in the fasting state and the end-tidal Pco2 was unchanged. It is concluded that

  12. A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

    NARCIS (Netherlands)

    Fardin, P.; Barla, A.; Mosci, S.; Rosasco, L.; Verri, A.; Versteeg, R.; Caron, H.N.; Molenaar, J.J.; Ora, I.; Eva, A.; Puppo, M.; Varesio, L.

    2010-01-01

    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 ab

  13. Biochemical and biomolecular aspects of oxidative stress due to acute and severe hypoxia in human muscle tissue.

    Science.gov (United States)

    Corbucci, G G; Sessego, R; Velluti, C; Salvi, M

    1995-01-01

    Mitochondrial oxidative stress was investigated in severe and acute hypoxia and in reperfusion applied to human muscle tissues. The biochemical and biomolecular relationship between the response of the respiratory-chain enzymic complexes and the metabolism of specific hypoxia stress proteins (HSP) suggest an adaptive mechanism which antagonizes the oxidative damage due to acute and severe tissue hypoxia.

  14. Hypoxia-inducible factor-1 alpha regulates the role of vascular endothelial growth factor on pulmonary arteries of rats with hypoxia-induced pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    李启芳; 戴爱国

    2004-01-01

    Background Hypoxia-inducible factor-1α (HIF-1α) is one of the pivotal mediators in the response of lungs to decreased oxygen availability, and increasingly has been implicated in the pathogenesis of pulmonary hypertension. Vascular endothelial growth factor (VEGF), a downstream target gene of HIF-1α, plays an important role in the pathogenesis of hypoxic pulmonary hypertension and hypoxic pulmonary artery remodelling. In this study, we investigated the dynamic expression of HIF-1α and VEGF in pulmonary artery of rats with hypoxia-induced pulmonary hypertension. Methods Forty male Wistar rats were exposed to hypoxia for 0, 3, 7, 14 or 21 days. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were estimated. Lungs were inflated and fixed for in situ hybridisation and immunohistochemistry. Results mPAP values were significantly higher than the control values after 7days of hypoxia [(18.4±0.4) mmHg, P<0.05]. RVHI developed significantly after 14 days of hypoxia. Expression of HIF-1α protein increased in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media, HIF-1α protein was markedly increased by day 3 (0.20±0.02, P<0.05), reached the peak by day 7, then declined after day 14 of hypoxia. HIF-1α mRNA increased significantly after day 14 of hypoxia (0.20±0.02, P<0.05). VEGF protein began to increase markedly after day 7 of hypoxia, reaching its peak around day 14 of hypoxia (0.15±0.02, P<0.05). VEGF mRNA began to increase after day 7 of hypoxia, then remained more or less stable from day 7 onwards. VEGF mRNA is located mainly in tunica intima and tunica media, whereas VEGF protein is located predominantly in tunica intima. Linear analysis showed that HIF-1α mRNA, VEGF and mPAP were correlated with hypoxic pulmonary artery remodelling. HIF-1α mRNA was positively correlated with VEGF mRNA and protein (P<0.01). Conclusion HIF-1α and VEGF are both involved in the

  15. Optimal ultrasonic array focusing in attenuative media.

    Science.gov (United States)

    Ganguli, A; Gao, R X; Liang, K; Jundt, J

    2011-12-01

    This paper presents a parametric study on the efficiency of ultrasound focusing in an attenuative medium, using phased arrays. Specifically, an analytical model of ultrasound wave focusing in a homogeneous, isotropic and attenuative fluid with point sources is presented. Calculations based on the model have shown that in an attenuative medium, an optimum frequency exists for the best focusing performance for a particular size of aperture and focal distance. The effect of different f numbers on the focusing performance in the attenuative medium is further investigated. The information obtained from the analytical model provides insights into the design and installation of a phased transducer array for energy efficient wave focusing.

  16. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Oliwia Alicja Janc

    2014-02-01

    Full Text Available Rett syndrome (RS causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2-/y hippocampus, confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3-5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved short-term plasticity, and fully restored synaptic long-term potentiation. Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

  17. Interleukin-1 receptor associated kinases-1/4 inhibition protects against acute hypoxia/ischemia-induced neuronal injury in vivo and in vitro.

    Science.gov (United States)

    Yang, Y-F; Chen, Z; Hu, S-L; Hu, J; Li, B; Li, J-T; Wei, L-J; Qian, Z-M; Lin, J-K; Feng, H; Zhu, G

    2011-11-24

    Neuronal Toll-like receptors (TLRs)-2 and -4 have been shown to play a pivotal role in ischemic brain injury, and the interleukin-1 receptor associated kinases (IRAKs) are considered to be the key signaling molecules involved downstream of TLRs. Here, we investigated the expression levels of IRAK-1 and -4 and the effects of IRAK-1/4 inhibition on brain ischemic insult and neuronal hypoxia-induced injury. Male Sprague-Dawley (SD) rats and the rat neuroblastoma B35 cell line were used in these experiments. Permanent middle cerebral artery occlusion (MCAO) was induced by the intraluminal filament technique, and B35 cells were stimulated with the hypoxia-mimetic, cobalt chloride (CoCl(2)). Following induction of hypoxia/ischemia (H/I), B35 cells and cerebral cortical neurons expressed higher levels of IRAK-1 and -4. Furthermore, IRAK-1/4 inhibition decreased the mortality rate, functional deficits, and ischemic infarct volume by 7 days after MCAO. Similarly, IRAK-1/4 inhibition attenuated CoCl(2)-induced cytotoxicity and apoptosis in B35 cells in vitro. Our results show that IRAK-1/4 inhibition decreased the nuclear translocation of the nuclear factor-kappaB (NF-κB) p65 subunit, the levels of activated (phosphorylated) c-jun N-terminal kinase (JNK) and cleaved caspase-3, and the secretion of TNF-α and IL-6 in B35 cells at 6 h after CoCl(2) treatment. These data suggest that IRAK-1/4 inhibition plays a neuroprotective role in H/I-induced brain injury.

  18. The Effects of the Active Hypoxia to the Speech Signal Inharmonicity

    Directory of Open Access Journals (Sweden)

    Z. N. Milivojevic

    2014-06-01

    Full Text Available When the people are climbing on the mountain, they are exposed to decreased oxygen concentration in the tissue, which is commonly called the active hypoxia. This paper addressed the problem of an acute hypoxia that affects the speech signal at the altitude up to 2500 m. For the experiment, the speech signal database that contains the articulation of vowels was recorded at different alti¬tudes. This speech signal was processed by the originally developed algorithm, which extracted the fundamental frequency and the inharmonicity coefficient. Then, they were subjected to the analysis in order to derive the effects of the acute hypoxia. The results showed that the hypoxia level can be determined by the change of the inharmonicity coefficient. Accordingly, the degree of hypoxia can be estimated.

  19. Lipopolysaccharide and Interleukin 1 Augment the Effects of Hypoxia and Inflammation in Human Pulmonary Arterial Tissue

    Science.gov (United States)

    Ziesche, Rolf; Petkov, Venzeslav; Williams, John; Zakeri, Schaker M.; Mosgoller, Wilhelm; Knofler, Martin; Block, Lutz H.

    1996-10-01

    The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor α on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1β , or tumor necrosis factor α augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

  20. Effects of 24-Epibrassinolide on Antioxidant System in Cucumber Seedling Roots Under Hypoxia Stress

    Institute of Scientific and Technical Information of China (English)

    KANG Yun-yan; GUO Shi-rong; LI Juan; DUAN Jiu-ju

    2007-01-01

    This article aims to study the effects of exogenous 24-epibrassinolide (EBR) on the changes in ROS, activities of antioxidative enzymes and antioxidants in cucumber (Cucumis sativus L.) seedling roots under hypoxia stress. Seedlings of a hypoxianormoxic or hypoxic nutrient solutions that were added or not added with 10-3 mg L-1 EBR. Under hypoxia stress, the ROS levels and the lipid peroxidation were significantly increased in the roots upon exposure to hypoxia stress, which were inhibited by EBR application. The EBR treatment significantly increased the seedlings growth and SOD, APX, GR activities, and contents of AsA and GSH under hypoxia stress. From the results obtained in this study, it can be concluded that oxidative damage on seedling roots by hypoxia stress can be considerably alleviated and the tolerance of plants was elevated.

  1. Temporal and topographic profiles of tissue hypoxia following transient focal cerebral ischemia in rats.

    Science.gov (United States)

    Noto, Takahisa; Furuichi, Yasuhisa; Ishiye, Masayuki; Matsuoka, Nobuya; Aramori, Ichiro; Mutoh, Seitaro; Yanagihara, Takehiko; Manabe, Noboru

    2006-08-01

    Intravascular accumulation of blood cells after brain ischemia-reperfusion can cause obstruction of cerebral blood flow and tissue hypoxia/ischemia as a consequence. In the present study, we examined temporal and topographic changes of tissue hypoxia/ischemia after occlusion of the middle cerebral artery (MCA) for 60 min in rats with immunohistochemical staining for hypoxia (2-nitroimidazole hypoxia marker: hypoxyprobe-1 adducts). Our results showed that tissue hypoxia expressed as positive staining for hypoxyprobe-1 adducts preceded neuronal degeneration. Platelets and granulocytes were detected close to the hypoxyprobe-1 adducts positive area. These results suggested that the hypoxic environment could persist even after reperfusion of MCA, because of vascular obstruction with accumulation of platelets and granulocytes.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  3. Anoxia- and hypoxia-induced expression of LDH-A* in the Amazon Oscar, Astronotus crassipinis

    Directory of Open Access Journals (Sweden)

    Vera Maria Fonseca Almeida-Val

    2011-01-01

    Full Text Available Adaptation or acclimation to hypoxia occurs via the modulation of physiologically relevant genes, such as erythropoietin, transferrin, vascular endothelial growth factor, phosphofructokinase and lactate dehydrogenase A. In the present study, we have cloned, sequenced and examined the modulation of the LDH-A gene after an Amazonian fish species, Astronotus crassipinis (the Oscar, was exposed to hypoxia and anoxia. In earlier studies, we have discovered that adults of this species are extremely tolerant to hypoxia and anoxia, while the juveniles are less tolerant. Exposure of juveniles to acute hypoxia and anoxia resulted in increased LDH-A gene expression in skeletal and cardiac muscles. When exposed to graded hypoxia juveniles show decreased LDH-A expression. In adults, the levels of LDH-A mRNA did not increase in hypoxic or anoxic conditions. Our results demonstrate that, when given time for acclimation, fish at different life-stages are able to respond differently to survive hypoxic episodes.

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

    Science.gov (United States)

    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.

  5. Hypoxia-inducible factor prolyl 4-hydroxylases regulating erythropoiesis, and hypoxia-inducible lysyl oxidase regulating skeletal muscle development during embryogenesis

    OpenAIRE

    Laitala, A. (Anu)

    2014-01-01

    Abstract Erythropoiesis is the process of red blood cell production. The main regulator is the erythropoietin (EPO) hormone, which is strongly upregulated in low oxygen concentration (hypoxia) in cells via the hypoxia-inducible transcription factor HIF. The stability of HIF is regulated in an oxygen-dependent manner by three HIF prolyl 4-hydroxylases, all of which are known to participate in the regulation of erythropoiesis. A role in erythropoiesis of a fourth prolyl 4-hydroxylase, P4H-TM...

  6. Wideband, 50 dB Attenuation Range Liquid Crystal Based Variable Optical Attenuator

    Institute of Scientific and Technical Information of China (English)

    J.J.; Pan; Henry; He; Eric; Zhang

    2003-01-01

    A compact variable optical attenuator, covering C and L bands with over 50 dB attenuation range, is realized using a single liquid crystal cell with a tilted fused silica coating compensating the cell's small residual birefringence.

  7. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species.

    Science.gov (United States)

    Goyal, Parag; Weissmann, Norbert; Grimminger, Friedrich; Hegel, Cornelia; Bader, Lucius; Rose, Frank; Fink, Ludger; Ghofrani, Hossein A; Schermuly, Ralph T; Schmidt, Harald H H W; Seeger, Werner; Hänze, Jörg

    2004-05-15

    Hypoxia sensing and related signaling events, including activation of hypoxia-inducible factor 1 (HIF-1), represent key features in cell physiology and lung function. Using cultured A549 cells, we investigated the role of NAD(P)H oxidase 1 (Nox1), suggested to be a subunit of a low-output NAD(P)H oxidase complex, in hypoxia signaling. Nox1 expression was detected on both the mRNA and protein levels. Upregulation of Nox1 mRNA and protein occurred during hypoxia, accompanied by enhanced reactive oxygen species (ROS) generation. A549 cells, which were transfected with a Nox1 expression vector, revealed an increase in ROS generation accompanied by activation of HIF-1-dependent target gene expression (heme oxygenase 1 mRNA, hypoxia-responsive-element reporter gene activity). In A549 cells stably overexpressing Nox1, accumulation of HIF-1alpha in normoxia and an additional increase in hypoxia were noted. Interference with ROS metabolism by the flavoprotein inhibitor diphenylene iodonium (DPI) and catalase inhibited HIF-1 induction. This suggests that H2O2 links Nox1 and HIF-1 activation. We conclude that hypoxic upregulation of Nox1 and subsequently augmented ROS generation may activate HIF-1-dependent pathways.

  8. Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans.

    Directory of Open Access Journals (Sweden)

    Audrey Bellier

    2009-12-01

    Full Text Available Pore-forming toxins (PFTs are by far the most abundant bacterial protein toxins and are important for the virulence of many important pathogens. As such, cellular responses to PFTs critically modulate host-pathogen interactions. Although many cellular responses to PFTs have been recorded, little is understood about their relevance to pathological or defensive outcomes. To shed light on this important question, we have turned to the only genetic system for studying PFT-host interactions-Caenorhabditis elegans intoxication by Crystal (Cry protein PFTs. We mutagenized and screened for C. elegans mutants resistant to a Cry PFT and recovered one mutant. Complementation, sequencing, transgenic rescue, and RNA interference data demonstrate that this mutant eliminates a gene normally involved in repression of the hypoxia (low oxygen response pathway. We find that up-regulation of the C. elegans hypoxia pathway via the inactivation of three different genes that normally repress the pathway results in animals resistant to Cry PFTs. Conversely, mutation in the central activator of the hypoxia response, HIF-1, suppresses this resistance and can result in animals defective in PFT defenses. These results extend to a PFT that attacks mammals since up-regulation of the hypoxia pathway confers resistance to Vibrio cholerae cytolysin (VCC, whereas down-regulation confers hypersusceptibility. The hypoxia PFT defense pathway acts cell autonomously to protect the cells directly under attack and is different from other hypoxia pathway stress responses. Two of the downstream effectors of this pathway include the nuclear receptor nhr-57 and the unfolded protein response. In addition, the hypoxia pathway itself is induced by PFT, and low oxygen is protective against PFT intoxication. These results demonstrate that hypoxia and induction of the hypoxia response protect cells against PFTs, and that the cellular environment can be modulated via the hypoxia pathway to

  9. A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.

    Science.gov (United States)

    Irshad, Khushboo; Mohapatra, Saroj Kant; Srivastava, Chitrangda; Garg, Harshit; Mishra, Seema; Dikshit, Bhawana; Sarkar, Chitra; Gupta, Deepak; Chandra, Poodipedi Sarat; Chattopadhyay, Parthaprasad; Sinha, Subrata; Chosdol, Kunzang

    2015-01-01

    Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

  10. A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance.

    Directory of Open Access Journals (Sweden)

    Khushboo Irshad

    Full Text Available Hypoxia is a hallmark of solid tumors including glioblastoma (GBM. Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2. Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

  11. Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils.

    Science.gov (United States)

    McGovern,