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Sample records for attenuates hypobaric hypoxia

  1. Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: Molecular mechanisms of action of cobalt chloride

    International Nuclear Information System (INIS)

    This study reports the efficacy of cobalt preconditioning in preventing hypobaric hypoxia induced vascular leakage (an indicator of cerebral edema) using male Sprague-Dawley rats as model system. Exposure of animals to hypobaric hypoxia led to a significant increase in vascular leakage, reactive oxygen species (ROS), nitric oxide (NO), and vascular endothelial growth factor (VEGF) levels. There was a marked increase in Nuclear Factor κB (NFκB) DNA binding activity and levels of pro-inflammatory cytokines such as Monocyte chemoattractant protein (MCP-1), Interferon-γ (IFN-γ), Interleukin-1 (IL-1), and Tumor Necrosis Factor-α (TNF-α) and cell adhesion molecules such as Vascular Cell Adhesion Molecule-1 (VCAM-1), and P-selectin. Chemical preconditioning by cobalt for 7 days (12.5 mg Co/kg b.w., oral) significantly attenuated cerebral vascular leakage and the expression of inflammatory mediators induced by hypoxia. Administration of NFκB inhibitor, curcumin (50 mg/kg b.w.; i.p.) appreciably inhibited hypoxia induced vascular leakage indicating the involvement of NFκB in causing vascular leakage. Interestingly, cobalt when administered at 12.5 mg Co/kg b.w. (i.p.), 1 h before hypoxia could not prevent the vascular leakage indicating that cobalt per se did not have an effect on NFκB. The lower levels of NFκB observed in the brains of cobalt administered animals might be due to higher levels of antioxidant and anti-inflammatory proteins (hemeoxygenase-1 and metallothionein). To conclude cobalt preconditioning inhibited hypobaric hypoxia induced cerebral vascular leakage by lowering NFκB DNA binding activity and its regulated pro-inflammatory mediators. This is contemplated to be mediated by cobalt induced reduction in ROS/NO and increase in HO-1 and MT

  2. Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

    Science.gov (United States)

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

    2011-01-01

    INTRODUCTION. Some manufacturers of reduced oxygen (O2) breathing devices claim a comparable hypobaric hypoxia (HH) training experience by providing F(sub I) O2 hypoxia (NH) as for HH exposures the devices ignore P(sub A)O2 and P(sub A)CO2 as more direct agents to induce signs and symptoms of hypoxia during acute training exposures. RESULTS. There is not a sufficient integrated physiological understanding of the determinants of P(sub A)O2 and P(sub A)CO2 under acute NH and HH given the same hypoxic pO2 to claim a device that provides isohypoxia. Isohypoxia is defined as the same distribution of hypoxia signs and symptoms under any circumstances of equivalent hypoxic dose, and hypoxic pO2 is an incomplete hypoxic dose. Some devices that claim an equivalent HH experience under NH conditions significantly overestimate the HH condition, especially when simulating altitudes above 10,000 feet (3,048 m). CONCLUSIONS. At best, the claim should be that the devices provide an approximate HH experience since they only duplicate the ambient pO2 at sea level as at altitude (iso-pO2 machines). An approach to reduce the overestimation is to at least provide machines that create the same P(sub I)O2 (iso-P(sub I)O2 machines) conditions at sea level as at the target altitude, a simple software upgrade.

  3. Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia.

    Science.gov (United States)

    Gola, Shefali; Keshri, Gaurav Km; Gupta, Asheesh

    2013-09-01

    Hypobaric hypoxia induced at high altitude causes a subnormal oxygen concentration in cells which affects the drug metabolic and pharmacokinetic (PK) capacity of the body. The metabolism and PK of drugs like ibuprofen may be impaired under hypoxia and may require a different than usual therapeutic dose regimen to ensure safe therapy. The present investigation was undertaken to evaluate the effect of acute hypobaric hypoxia (AHH) on hepatic metabolism and PK of ibuprofen in rats. Animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for AHH exposure (6 and 24 h) in a decompression chamber and were administrated with single dose of ibuprofen (80 mg/kg body weight, p.o.). The results showed that GST activity was significantly reduced at 6 h (15%) and 24 h (23%) (pibuprofen exhibited significant increase by 42% and 51% (pibuprofen however, it requires further investigation under chronic hypobaric hypoxic conditions.

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

    Directory of Open Access Journals (Sweden)

    Neuhaus C

    2014-11-01

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

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

    OpenAIRE

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

    2016-01-01

    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...

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

    Science.gov (United States)

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

    2016-01-01

    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 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. PMID:27130215

  7. 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.

  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

    Institute of Scientific and Technical Information of China (English)

    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. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.

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    Kauser, H; Sahu, S; Kumar, S; Panjwani, U

    2014-01-17

    Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH. PMID:24184415

  11. Proteomic identification of novel differentiation plasma protein markers in hypobaric hypoxia-induced rat model.

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    Yasmin Ahmad

    Full Text Available BACKGROUND: Hypobaric hypoxia causes complex changes in the expression of genes, including stress related genes and corresponding proteins that are necessary to maintain homeostasis. Whereas most prior studies focused on single proteins, newer methods allowing the simultaneous study of many proteins could lead to a better understanding of complex and dynamic changes that occur during the hypobaric hypoxia. METHODS: In this study we investigated the temporal plasma protein alterations of rat induced by hypobaric hypoxia at a simulated altitude of 7620 m (25,000 ft, 282 mm Hg in a hypobaric chamber. Total plasma proteins collected at different time points (0, 6, 12 and 24 h, separated by two-dimensional electrophoresis (2-DE and identified using matrix assisted laser desorption ionization time of flight (MALDI-TOF/TOF. Biological processes that were enriched in the plasma proteins during hypobaric hypoxia were identified using Gene Ontology (GO analysis. According to their properties and obvious alterations during hypobaric hypoxia, changes of plasma concentrations of Ttr, Prdx-2, Gpx -3, Apo A-I, Hp, Apo-E, Fetub and Nme were selected to be validated by Western blot analysis. RESULTS: Bioinformatics analysis of 25 differentially expressed proteins showed that 23 had corresponding candidates in the database. The expression patterns of the eight selected proteins observed by Western blot were in agreement with 2-DE results, thus confirming the reliability of the proteomic analysis. Most of the proteins identified are related to cellular defense mechanisms involving anti-inflammatory and antioxidant activity. Their presence reflects the consequence of serial cascades initiated by hypobaric hypoxia. CONCLUSION/SIGNIFICANCE: This study provides information about the plasma proteome changes induced in response to hypobaric hypoxia and thus identification of the candidate proteins which can act as novel biomarkers.

  12. 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.

  13. 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 heal...

  14. Consequences of Longterm-Confinement and Hypobaric Hypoxia on Immunity in the Antarctic Concordia Environment

    Science.gov (United States)

    Crucian, Brian; Chouker, Alexander; Pierson, Duane; Mehta, Satish; Stowe, Raymond; Salam, Alex; Sams, Clarence

    2010-01-01

    This slide presentation reviews the affects of longterm-confinement and hypobaric hypoxia on immunity in the Antarctic Concordia environment. It includes information on spaceflight-associated immune dysregulation, immune-related knowledge gaps, and ground-based space flight analogs.

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

    Science.gov (United States)

    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.

    Directory of Open Access Journals (Sweden)

    Belén Feriche

    Full Text Available When ascending to a higher altitude, changes in air density and oxygen levels affect the way in which explosive actions are executed. This study was designed to compare the effects of acute exposure to real or simulated moderate hypoxia on the dynamics of the force-velocity relationship observed in bench press exercise. Twenty-eight combat sports athletes were assigned to two groups and assessed on two separate occasions: G1 (n = 17 in conditions of normoxia (N1 and hypobaric hypoxia (HH and G2 (n = 11 in conditions of normoxia (N2 and normobaric hypoxia (NH. Individual and complete force-velocity relationships in bench press were determined on each assessment day. For each exercise repetition, we obtained the mean and peak velocity and power shown by the athletes. Maximum power (Pmax was recorded as the highest P(mean obtained across the complete force-velocity curve. Our findings indicate a significantly higher absolute load linked to P(max (∼ 3% and maximal strength (1 RM (∼ 6% in G1 attributable to the climb to altitude (P<0.05. We also observed a stimulating effect of natural hypoxia on P(mean and P(peak in the middle-high part of the curve (≥ 60 kg; P<0.01 and a 7.8% mean increase in barbell displacement velocity (P<0.001. No changes in any of the variables examined were observed in G2. According to these data, we can state that acute exposure to natural moderate altitude as opposed to simulated normobaric hypoxia leads to gains in 1 RM, movement velocity and power during the execution of a force-velocity curve in bench press.

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

    Science.gov (United States)

    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 (P<0.05). We also observed a stimulating effect of natural hypoxia on P(mean) and P(peak) in the middle-high part of the curve (≥ 60 kg; P<0.01) and a 7.8% mean increase in barbell displacement velocity (P<0.001). No changes in any of the variables examined were observed in G2. According to these data, we can state that acute exposure to natural moderate altitude as opposed to simulated normobaric hypoxia leads to gains in 1 RM, movement velocity and power during the execution of a force-velocity curve in bench press. PMID:25474104

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

    Science.gov (United States)

    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.

  19. Effects of physical training on pulmonary arterial pressure during exercise under hypobaric hypoxia in rats

    Science.gov (United States)

    Kashimura, Osamu; Sakai, Akio

    1991-12-01

    In this investigation, we assessed the effects of physical training on exercise-induced systemic and pulmonary hemodynamic changes under hypobaric hypoxia in catheter-implanted rats. We made continuous measurements of pulmonary and systemic arterial pressures during progressive treadmill exercises under hypobaric hypoxia (equivalent to altitudes of 2500 and 5500 m) in 46 control and 41 trained rats. Trained rats were exercised on two running schedules: 4 weeks (4-trained) and 6 weeks (6-trained). Both these groups of trained rats were exercised for the same length of running time each day. The increase in resting mean pulmonary arterial pressure(overline {P_{pa} } ) with increasing equivalent altitude was lower in the two trained groups than in the control group. The increase in(overline {P_{pa} } ) with progressive intensity of exercise was lower in the 6-trained than in the 4-trained and control groups at 610 and 2500 m. The 6-trained rats showed higher pH, P a CO 2 and O2 saturation in their blood than did the control group, whereas the P a O 2 was less. Lung tissue cyclic AMP concentration at rest was higher in the 6-trained than in the control group. Finally, it may be noted that exercise-induced lung tissue vasodilator responses seem to be enhanced in well-trained rats under both normobaric normoxia and hypobaric hypoxia. This study indicates that exercise training may be useful in preventing pulmonary hypertension resulting from both hypoxia and exercise.

  20. Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation

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    Arya A

    2013-11-01

    Full Text Available Aditya Arya,1 Niroj Kumar Sethy,1 Sushil Kumar Singh,2 Mainak Das,3 Kalpana Bhargava1 1Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Delhi, 2Functional Materials Division, Solid State Physics Laboratory, Defence Research and Development Organization, Delhi, 3Biological Science and Bioengineering, Indian Institute of Technology, Kanpur, Uttar Pradesh, India Background: Cerium oxide nanoparticles (nanoceria are effective at quenching reactive oxygen species (ROS in cell culture and animal models. Although nanoceria reportedly deposit in lungs, their efficacy in conferring lung protection during oxidative stress remains unexplored. Thus, the study evaluated the protective efficacy of nanoceria in rat lung tissue during hypobaric hypoxia. Methods: A total of 48 animals were randomly divided into four equal groups (control [C], nanoceria treated [T], hypoxia [H], and nanoceria treated plus hypoxia [T+H]. Animals were injected intraperitoneally with either a dose of 0.5 µg/kg body weight/week of nanoceria (T and T+H groups or vehicle (C and H groups for 5 weeks. After the final dose, H and T+H animals were challenged with hypobaric hypoxia, while C and T animals were maintained at normoxia. Lungs were isolated and homogenate was obtained for analysis of ROS, lipid peroxidation, glutathione, protein carbonylation, and 4-hydroxynonenal-adduct formation. Plasma was used for estimating major inflammatory cytokines using enzyme-linked immunosorbent assay. Intact lung tissues were fixed and both transmission electron microscopy and histopathological examinations were carried out separately for detecting internalization of nanoparticles as well as altered lung morphology. Results: Spherical nanoceria of 7–10 nm diameter were synthesized using a microemulsion method, and the lung protective efficacy of the nanoceria evaluated during hypobaric hypoxia. With repeated

  1. 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

  2. The effects of acute intermittent hypoxia on cardiovascular parameters in normotensive and chronic hypobaric hypoxia-induced hypertensive rabbits.

    Science.gov (United States)

    Yaman, Muhittin O; Guner, Ibrahim; Uzun, Hafize; Sahin, Gulderen; Yelmen, Nermin

    2014-01-01

    The effects of both chronic hypoxia and acute intermittent hypoxia (AIH) on cardiovascular system are unclear. We designed this study to develop a rabbit model of hypertension by exposure to chronic hypobaric hypoxia (CHH) and to investigate the effects of AIH on hypertensive rabbits. Present study was performed in 13 albino rabbits that divided into CHH and control groups. To develop hypertension, the rabbits were placed in a hypobaric chamber (390 mmHg; 22 hours/day, 30 days). Afterwards, AIH protocol was applied (8% FIO2 (Fraction of Inspired Oxygen) 1 min + 5 min normoxia, 20 cycles, 2 hours) to rabbits anesthetized with urethane and alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR) and hematocrit values have been determined. Also asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 and norepinephrine values have been analyzed in blood. We developed a model of hypertension in rabbits via exposure to severe CHH and we believe that ADMA is an important parameter in the development and permanence of CHH-induced hypertension. The main finding of this sudy was the depressor effect of AIH on blood pressure and heart rate in CHH- induced hypertension model. Finally, we believe that AIH protocol may be applicable for prevention and treatment of hypertension if properly developed. PMID:24448370

  3. Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

    OpenAIRE

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

    2015-01-01

    Kanekar, Shami, Olena V. Bogdanova, Paul R. Olson, Young-Hoon Sung, Kristen E. D'Anci, and Perry F. Renshaw. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not males. High Alt Med Biol 16:52–60, 2015—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 lo...

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. Hypobaric-hypoxia induces alteration in microbes and microbes-associated enzyme profile in rat colonic samples.

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    Maity, Chiranjit; Lahiri, Pallavi; Adak, Atanu; Ghosh, Kuntal; Pati, Bikas R; Mondal, Keshab C

    2013-10-01

    Present study deals with the straight impact of hypobaric hypoxia on the quantity and composition of some predominant fecal microflora and its functional aspects. For that, isolated fecal contents of rat were exposed to two different simulated air pressures (70 kPa and 40 kPa) for different time durations (1, 3, and 5 h) and the bacterial community composition was compared with normobaric groups (101.3 kPa). It was found that the total anaerobes, Escherichia coli, Enterbacters spp., Bifidobacterium spp., Clostridium spp. were increased whereas total aerobes were decreased at both hypobaric treatments. The increased number of amplicon was detected in the pressure-treated groups than the control that clearly mentioned the disruption of microbiota structure at different simulated hypobaric-hypoxia. The amylase, protease, tannase, β-glucuronidase, and alkaline phosphatase activities were increased at these atmospheric pressures. Thus, the present investigation demonstrates that the hypobaric hypoxia is an important environmental factor which can strongly modulate the composition of intestinal flora as well as microflora-derived functional aspects. PMID:24215884

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

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    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.

  8. Effect of Acute Dietary Nitrate Consumption on Oxygen Consumption During Submaximal Exercise in Hypobaric Hypoxia.

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    Carriker, Colin R; Mermier, Christine M; Van Dusseldorp, Trisha A; Johnson, Kelly E; Beltz, Nicholas M; Vaughan, Roger A; McCormick, James J; Cole, Nathan H; Witt, Christopher C; Gibson, Ann L

    2016-08-01

    Reduced partial pressure of oxygen impairs exercise performance at altitude. Acute nitrate supplementation, at sea level, may reduce oxygen cost during submaximal exercise in hypobaric hypoxia. Therefore, we investigated the metabolic response during exercise at altitude following acute nitrate consumption. Ten well-trained (61.0 ± 7.4 ml/kg/min) males (age 28 ± 7 yr) completed 3 experimental trials (T1, T2, T3). T1 included baseline demographics, a maximal aerobic capacity test (VO2max) and five submaximal intensity cycling determination bouts at an elevation of 1600 m. A 4-day dietary washout, minimizing consumption of nitrate-rich foods, preceded T2 and T3. In a randomized, double-blind, placebo-controlled, crossover fashion, subjects consumed either a nitrate-depleted beetroot juice (PL) or ~12.8 mmol nitrate rich (NR) beverage 2.5 hr before T2 and T3. Exercise at 3500 m (T2 and T3) via hypobaric hypoxia consisted of a 5-min warm-up (25% of normobaric VO2max) and four 5-min cycling bouts (40, 50, 60, 70% of normobaric VO2max) each separated by a 4-min rest period. Cycling RPM and watts for each submaximal bout during T2 and T3 were determined during T1. Preexercise plasma nitrite was elevated following NR consumption compared with PL (1.4 ± 1.2 and 0.7 ± 0.3 uM respectively; p exercise at 3500 m does not reduce oxygen cost but may reduce blood lactate accumulation at lower intensity workloads. PMID:26630309

  9. 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.

  10. 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.

  11. 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.

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

    Science.gov (United States)

    Kushwah, Neetu; Jain, Vishal; Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

  13. 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. PMID:25803141

  14. 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.

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

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    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

  16. [Effects of acute hypobaric hypoxia and exhaustive exercise on AMP-activated protein kinase phosphorylation in rat skeletal muscle].

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    Yang, Tao; Huang, Qing-Yuan; Shan, Fa-Bo; Guan, Li-Bin; Cai, Ming-Chun

    2012-04-25

    The present study was aimed to explore the changes of phosphorylated AMP-activated protein kinase (pAMPK) level in skeletal muscle after exposure to acute hypobaric hypoxia and exhaustive exercise. Thirty-two male Sprague-Dawley (SD) rats were randomly divided into sea level and high altitude groups. The rats in high altitude group were submitted to simulated 5 000 m of high altitude in a hypobaric chamber for 24 h, and sea level group was maintained at normal conditions. All the rats were subjected to exhaustive swimming exercise. The exhaustion time was recorded. Before and after the exercise, blood lactate and glycogen content in skeletal muscle were determined; AMPK and pAMPK levels in skeletal muscle were detected by Western blot. The results showed that the exhaustion time was significantly decreased after exposure to high altitude. At the moment of exhaustion, high altitude group had lower blood lactate concentration and higher surplus glycogen content in gastrocnemius compared with sea level group. Exhaustive exercise significantly increased the pAMPK/AMPK ratio in rat skeletal muscles from both sea level and high altitude groups. However, high altitude group showed lower pAMPK/AMPK ratio after exhaustion compared to sea level group. These results suggest that, after exposure to acute hypobaric hypoxia, the decrement in exercise capacity may not be due to running out of glycogen, accumulation of lactate or disturbance in energy status in skeletal muscle. PMID:22513470

  17. Cardioprotective adaptation of rats to intermittent hypobaric hypoxia is accompanied by the increased association of hexokinase with mitochondria.

    Science.gov (United States)

    Waskova-Arnostova, Petra; Elsnicova, Barbara; Kasparova, Dita; Hornikova, Daniela; Kolar, Frantisek; Novotny, Jiri; Zurmanova, Jitka

    2015-12-15

    Chronic hypoxia increases the myocardial resistance to acute ischemia-reperfusion injury by affecting the mitochondrial redox balance. Hexokinase (HK) bears a high potential to suppress the excessive formation of reactive oxygen species because of its increased association with mitochondria, thereby inhibiting the membrane permeability transition pore opening and preventing cell death. The purpose of this study was to determine the effect of severe intermittent hypobaric hypoxia (7,000 m, 8 h/day, 5 wk) on the function and colocalization of HK isoforms with mitochondria in the left (LV) and right ventricles of rat myocardium. The real-time RT-PCR, Western blot, enzyme coupled assay, and quantitative immunofluorescence techniques were used. Our results showed significantly elevated expression of HK isoforms (HK1 and HK2) in the hypoxic LV. In addition, intermittent hypoxia increased the total HK activity and the association of HK isoforms with mitochondria in both ventricles. These findings suggest that HK may contribute to the cardioprotective phenotype induced by adaptation to severe intermittent hypobaric hypoxia. PMID:26494452

  18. Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude.

    Science.gov (United States)

    Gola, Shefali; Gupta, Asheesh; Keshri, Gaurav K; Nath, Madhu; Velpandian, Thirumurthy

    2016-03-20

    With studies indicative of altered drug metabolism and pharmacokinetics (DMPK) under high altitude (HA)-induced hypobaric hypoxia, consideration of better therapeutic approaches has continuously been aimed in research for HA related illness management. DMPK of drugs like ibuprofen may get affected under hypoxia which establishes the requirement of different therapeutic dose regimen to ensure safe and effective therapy at HA. This study examined the effects of the chronic hypobaric hypoxia (CHH) on hepatic DMPK of ibuprofen in rats. Experimental animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for CHH exposure (7 or 14 days) in decompression chamber and administered with ibuprofen (80 mg/kg, body weight, p.o.). Results demonstrated that CHH significantly altered PK variables of ibuprofen and activities of both phase-I and II hepatic metabolic enzymes as compared to the animals under normoxic conditions. Hepatic histopathological observations also revealed marked alterations. Increase in pro-inflammatory cytokines/chemokines viz. IL-1β, IL-2, IFN-γ, TNF-α exhibited close relevance with diminished CYP2C9 expression under CHH. Moreover, the down-regulated CYP2C9 level further supported the underlying mechanism for reduced metabolism of ibuprofen and as a result, increased retention of parent drug in the system. Increased mean retention time, Vd, T½ of ibuprofen, and decreased AUC, Cmax and clearance during CHH further strengthened the present findings. In conclusion, CHH exposure significantly affects hepatic DMPK of ibuprofen, which may further influence the usual therapeutic dose-regimen. Further, there is requirement of human studies to evaluate their susceptibility toward hypobaric hypoxia.

  19. 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

  20. 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.

  1. 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.

  2. Behavioural, brain and cardiac responses to hypobaric hypoxia in broiler chickens.

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    Martin, Jessica E; Christensen, Karen; Vizzier-Thaxton, Yvonne; Mitchell, Malcolm A; McKeegan, Dorothy E F

    2016-09-01

    A novel approach to pre-slaughter stunning of chickens has been developed in which birds are rendered unconscious by progressive hypobaric hypoxia. Termed Low Atmospheric Pressure Stunning (LAPS), this approach involves application of gradual decompression lasting 280s according to a prescribed curve. We examined responses to LAPS by recording behaviour, electroencephalogram (EEG) and electrocardiogram (ECG) in individual male chickens, and interpreted these with regard to the welfare impact of the process. We also examined the effect of two temperature adjusted pressure curves on these responses. Broiler chickens were exposed to LAPS in 30 triplets (16 and 14 triplets assigned to each pressure curve). In each triplet, one bird was instrumented for recording of EEG and ECG while the behaviour of all three birds was observed. Birds showed a consistent sequence of behaviours during LAPS (ataxia, loss of posture, clonic convulsions and motionless) which were observed in all birds. Leg paddling, tonic convulsions, slow wing flapping, mandibulation, head shaking, open bill breathing, deep inhalation, jumping and vocalisation were observed in a proportion of birds. Spectral analysis of EEG responses at 2s intervals throughout LAPS revealed progressive decreases in median frequency at the same time as corresponding progressive increases in total power, followed later by decreases in total power as all birds exhibited isoelectric EEG and died. There was a very pronounced increase in total power at 50-60s into the LAPS cycle, which corresponded to dominance of the signal by high amplitude slow waves, indicating loss of consciousness. Slow wave EEG was seen early in the LAPS process, before behavioural evidence of loss of consciousness such as ataxia and loss of posture, almost certainly due to the fact that it was completely dark in the LAPS chamber. ECG recordings showed a pronounced bradycardia (starting on average 49.6s into LAPS), often associated with arrhythmia, until

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

  5. Time course of endocrine changes in the hypophysis-gonad axis induced by hypobaric hypoxia in male rats.

    Science.gov (United States)

    Farias, Jorge Gonzalo; Bustos-Obregón, Eduardo; Tapia, Pablo Jose; Gutierrez, Eduardo; Zepeda, Andrea; Juantok, Camila; Cruz, Gonzalo; Soto, Gustavo; Benites, Julio; Reyes, Juan Guillermo

    2008-02-01

    Chronic hypobaric hypoxia (CHH) induces a decrease in sperm output and spermatogenesis in male rats. The mechanisms that underlie these changes in testicular function are unknown and could involve changes in the hypophysis-gonad axis. We have tested the hypothesis that changes take place in the endocrine status (FSH, follicle stimulating hormone; LH, luteinizing hormone; testosterone) of rats subjected to CHH. Male Wistar rats were maintained under normobaric or hypobaric conditions (428 torr, 4,600 m). On days 0, 5, 15 and 30 post-exposure, 12 rats were anesthetized, their body weights were measured and blood samples were collected. The testicles were fixed in 4% formaldehyde and processed for histological analysis. In this time course, the FSH levels rose by day 5 post-exposure. On subsequent days, the FSH levels decreased in rats subjected to CHH with a tendency to remain higher than the normoxic group. The LH plasma levels decreased in rats exposed to CHH. Consistent with the decrease in LH levels, the plasma testosterone level decreased significantly after 30 days of CHH exposure. Integrated analysis of hormonal changes in rats subjected to CHH and the body dehydration that occurs in HH allows us to conclude that the effects of CHH on spermatogenesis may be partially related to changes in the hypophysis-gonad hormonal axis. PMID:17984574

  6. S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

    Science.gov (United States)

    Chawla, Sonam; Rahar, Babita; Saxena, Shweta

    2016-05-01

    Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016. PMID:26959531

  7. Influence of in vivo hypobaric hypoxia on function of lymphocytes, neutrocytes, natural killer cells, and cytokines

    DEFF Research Database (Denmark)

    Klokker, M; Kharazmi, A; Galbo, H;

    1993-01-01

    of an increased concentration of lymphocytes. The absolute and relative concentration of CD16+ natural killer (NK) cells increased markedly during hypoxia and returned to pretest values after 2 h of recovery. The NK cell activity of blood mononuclear cells (BMNC, %lysis/fixed no. of BMNC) boosted with interferon......-alpha, interleukin-2 (IL-2), and indomethacin rose in parallel with unboosted NK cell activity during hypoxia. The percentage of CD4+ and CD8+ cells declined during hypoxia, whereas the absolute concentration of both CD8+ cells and CD14+ monocytes increased. Although the BMNC composition varied, the proliferative....... The chemiluminescence response of neutrocytes increased 2 h after hypoxia. It was concluded that acute hypoxia induced marked alterations in the immune system and that the NK cells are especially sensitive to the hypoxic stimulus....

  8. 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

  9. Naproxen, a Nonsteroidal Anti-Inflammatory Drug, Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats.

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

    2016-06-01

    Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS. PMID:26894935

  10. Prolonged hypobaric hypoxemia attenuates vasopressin secretion and renal response to osmostimulation in men

    DEFF Research Database (Denmark)

    Bestle, Morten H; Olsen, Niels Vidiendal; Poulsen, Troels D;

    2002-01-01

    Effects of hypobaric hypoxemia on endocrine and renal parameters of body fluid homeostasis were investigated in eight normal men during a sojourn of 8 days at an altitude of 4,559 m. Endocrine and renal responses to an osmotic stimulus (5% hypertonic saline, 3.6 ml/kg over 1 h) were investigated ...

  11. 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

    investigated, pre- and post-exposure, in ten young subjects, by 2-D DIGE and MS. Ten milligram biopsies were obtained from the mid part of the vastus lateralis muscle at sea level (control) and at altitude, after 7-9 days hypoxia. Differential analysis indicates that proteins involved in iron transport...

  12. 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...

  13. Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

    OpenAIRE

    Pichler Hefti, Jacqueline Renée; Sonntag, Denise; Hefti, Urs; Risch, Lorenz; Schoch, Otto D; Turk, Alexander J; Hess, Thomas; Bloch, Konrad E; Maggiorini,Marco; Merz, Tobias Michael; Weinberger, Klaus M.; Huber, Andreas R

    2013-01-01

    Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an ...

  14. Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators

    OpenAIRE

    Pichler Hefti, Jacqueline; Sonntag, Denise; Hefti, Urs; Risch, Lorenz; Schoch, Otto D; Turk, Alexander J; Hess, Thomas; Bloch, Konrad E; Maggiorini,Marco; Merz, Tobias M; Weinberger, Klaus M.; Huber, Andreas R

    2013-01-01

    Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an incr...

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

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    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.

  16. The effect of 10 days of heat acclimation on exercise performance in acute hypobaric hypoxia (4350 m).

    Science.gov (United States)

    White, Ailish C; Salgado, Roy M; Astorino, Todd A; Loeppky, Jack A; Schneider, Suzanne M; McCormick, James J; McLain, Trisha A; Kravitz, Len; Mermier, Christine M

    2016-01-01

    To examine the effect ("cross-tolerance") of heat acclimation (HA) on exercise performance upon exposure to acute hypobaric hypoxia (4350 m). Eight male cyclists residing at 1600 m performed tests of maximal aerobic capacity (VO2max) at 1600 m and 4350 m, a 16 km time-trial at 4350 m, and a heat tolerance test at 1600 m before and after 10 d HA at 40°C, 20% RH. Resting blood samples were obtained pre-and post- HA to estimate changes in plasma volume (ΔPV). Successful HA was indicated by significantly lower exercise heart rate and rectal temperature on day 10 vs. day 1 of HA and during the heat tolerance tests. Heat acclimation caused a 1.9% ΔPV, however VO2max was not significantly different at 1600 m or 4350 m. Time-trial cycling performance improved 28 sec after HA (p = 0.07), suggesting a possible benefit for exercise performance at acute altitude and that cross-tolerance between these variables may exist in humans. These findings do not clearly support the use of HA to improve exercise capacity and performance upon acute hypobaric hypoxia, however they do indicate that HA is not detrimental to either exercise capacity or performance. PMID:27227084

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Hypoxia attenuates anti-Aspergillus fumigatus immune responses initiated by human dendritic cells.

    Science.gov (United States)

    Fliesser, Mirjam; Wallstein, Marion; Kurzai, Oliver; Einsele, Hermann; Löffler, Jürgen

    2016-08-01

    Aspergillus fumigatus is an opportunistic mould that causes invasive pulmonary aspergillosis (IPA), a life-threatening infection in immunocompromised patients. During the course of IPA, localised areas of tissue hypoxia occur. Bacterial infection models revealed that hypoxic microenvironments modulate the function of host immune cells. However, the influence of hypoxia on anti-fungal immunity has been largely unknown. We evaluated the impact of hypoxia on the human anti-A. fumigatus immune response. Human monocyte-derived dendritic cells (DCs) were stimulated in vitro with germ tubes of A. fumigatus under normoxia or hypoxia (1% O2 ), followed by analysis of DC viability, maturation and cytokine release. While DC viability was unaffected, hypoxia attenuated cytokine release from DCs and maturation of DCs upon stimulation with A. fumigatus. These data suggest that hypoxia at the site of A. fumigatus infection inhibits full activation and function of human DCs. Thereby, this study identified hypoxia as a crucial immune-modulating factor in the human anti-fungal immune response that might influence the course and outcome of IPA in immunocompromised patients. PMID:27005862

  3. 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 < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly (P < 0.001). These changes remained significant at day 43 We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of 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.

  4. 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). PMID:22106819

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

    Directory of Open Access Journals (Sweden)

    Eileen M Bauer

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

  6. Mechanism research for the resistant effects of Saussurea involucrate cultured cell extracts on acute hypobaric hypoxia%雪莲培养细胞提取物的抗急性低压缺氧作用机制研究

    Institute of Scientific and Technical Information of China (English)

    周湘洁; 邸敏; 张丽芬; 杜学礼; 赵华丽; 钟悦; 尚颖; 周晓春; 郭志刚

    2015-01-01

    Objective To investigate the resistance to acute hypobaric hypoxia of Saussurea involucrata cultured cell extracts and the underlying mechanism.Methods Thirty-six Wistar rats were averagely divided into blank control group,negative control group and Saussurea involucrate cultured cell extracts group according to random number table.The Saussurea involucrate cultured cell extracts were infused to the rats of Saussurea involucrate cultured cell extracts group with the dose of 500 mg/kg for 14 d while the distilled water was fed to other 2 groups in the period.Except blank control group,the rats of other groups were exposed in simulative 8 000 m altitude experiencing acute hypobaric hypoxia after 14 d infusion.Then the rats of all groups were killed and sampled blood serum and brain tissue.The changes of various biochemical factors in brain tissue and blood serum,such as glutamic acid (GLU),lactic acid (LD),lactate dehydrogenase (LDH),malondialdehyde (MDA),total antioxidant capacity (T-AOC) and glutathion peroxidase (GSH-PX) were tested.Results Comparing with those of blank control group,the GLU,NO,LD,LDH and MDA in blood serum and brain tissue of negative control group were significantly increased (P<0.01),and Na+-K+-ATPase,Ca2+ Mg2+-ATPase,TAOC,SOD and GSH-PX were significantly decreased (P<0.01).The GLU,NO,LD,LDH and MDA of Saussurea involucrate cultured cell extracts group were significantly lower than those of negative control group (P<0.01) but with significantly higher Na+-K +-ATPase,Ca2+-Mg2 +-ATPase,T-AOC,SOD and GSH-PX (P<0.01).Conclusions For simulated 8 000 m hypoxia exposure,Saussurea involucrata cultured cell extracts can effectively remove or inhibit the generation of excessive oxygen free radicals and may prevent glutamic acid and lactic acid from accumulating in rat brain tissue and blood serum.By protecting the function of Na-K+-ATPase and Ca2+-Mg2+-ATPase on cell membrane and preventing the consequent toxic reaction induced by energy

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice.

    Science.gov (United States)

    Yu, Lixia; Chen, Yuan; Wang, Weiguang; Xiao, Zhonghai; Hong, Yan

    2016-08-01

    Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia. PMID:27497480

  12. LIPOPOLYSACCHARIDE ATTENUATES PHRENIC LONG-TERM FACILITATION FOLLOWING ACUTE INTERMITTENT HYPOXIA

    OpenAIRE

    Vinit, Stéphane; Windelborn, James A; Mitchell, Gordon S.

    2011-01-01

    Lipopolysaccharide (LPS) induces inflammatory responses, including microglial activation in the central nervous system. Since LPS impairs certain forms of hippocampal and spinal neuroplasticity, we hypothesized that LPS would impair phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) in outbred Sprague-Dawley (SD) and inbred Lewis (L) rats.. Approximately three hours following a single LPS injection (i.p.), the phrenic response during hypoxic episodes is reduced i...

  13. [The role of preventing nitric oxide deficiency in the antihypertensive effect of adaptation to hypoxia].

    Science.gov (United States)

    Mashina, S Iu; Smirin, B V; Pokidyshev, D A; Malyshev, I Iu; Liamina, N P; Senchikin, V N; Markov, Kh M; Manukhin, E B

    2001-01-01

    Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. Adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5-6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate a significant role of correction of endothelial NO deficiency in the antihypertensive effect of adaptation to hypoxia. PMID:15926321

  14. 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

  15. 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.

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

    DEFF Research Database (Denmark)

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

    2001-01-01

    , 459, and 404 mmHg) in a hypobaric chamber and while breathing 9% O(2) in N(2). These conditions were equivalent to altitudes of 3300, 4300, 5300, and 6300 m above sea level, respectively. At 4300 m, maximal exercise was also repeated after 4 and 8 h. Peak heart rate (HR) decreased from 191 (182......The purpose of the present study was to investigate the degree to which peak heart rate is reduced during exhaustive exercise in acute hypoxia. Five sea-level lowlanders performed maximal exercise at normobaric normoxia and at three different levels of hypobaric hypoxia (barometric pressures of 518...

  17. Characteristics of fat metabolism in skeletal muscle of rats after hypobaric hypoxic acclimation

    Institute of Scientific and Technical Information of China (English)

    Mao Sunzhong; Gao Yuqi; Chen Jian; Liu Fuyi; Gao Wenxiang; Huang Jian; Liao Weigong; Cai Mingchun

    2008-01-01

    Objective: To investigate the characteristics of fat metabolism in rat skeletal muscle after hypobaric hypoxia acclimation. Methods: Sprague-Dawley rats were divided into 3 groups randomly: control group (H0), hypoxic 5-day group (H5), and hypoxic 15-day group (HI5). Animals of H5 and 15 groups were exposed to hypobaric hypoxia chamber simulating 5 000 m high altitude for 5 d or 15 d respectively, 23 h per day. H0 group stayed outside of chamber.The level of fatty acid oxidation and uptake, and glucose oxidation were examined, and the level of non-esterified fatty acids (NEFA), ATP and phosphocreatine (PCr) were also assayed in rat skeletal muscles. Results: The contents of ATP and PCr in H5 group were lower than those in H0 and H15 groups (P<0.05), while there was no significant difference between H0 and H15. Compared with H0, the blood NEFA level in all hypoxia groups was increased significantly (P<0.05). The muscle NEFA level in HI5 group was greatly higher than that in H0 and H5 groups. The rates of fatty acid oxidation and uptake in H15 group were significantly higher than those in H0 and H5 groups (P<0.05), and the rate of glucose oxidation in all hypoxia groups was significantly decreased than that in H0 group (P<0.05). Conclusion: It is concluded that the enhanced fat oxidation may be one of the mechanisms in the maintenance of energy homeostasis after hypobaric hypoxic acclimation.

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

    Directory of Open Access Journals (Sweden)

    Héctor González-Pacheco

    2014-01-01

    Full Text Available 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.

  19. Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

    Science.gov (United States)

    Carreras, Alba; Zhang, Shelley X L; Almendros, Isaac; Wang, Yang; Peris, Eduard; Qiao, Zhuanhong; Gozal, David

    2015-02-01

    Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea. PMID:25406018

  20. Effect of eszopiclone on pentobarbital sodium-induced sleeping time in acute hypobaric hypoxia mice%右佐匹克隆对急性低压低氧小鼠戊巴比妥钠睡眠时间和自发活动的影响

    Institute of Scientific and Technical Information of China (English)

    钟玲; 宋永斌; 杨俊; 蔡倩; 徐江涛

    2014-01-01

    目的 评估右佐匹克隆(Eszopiclone,ESZ)对急性低压低氧小鼠戊巴比妥钠睡眠时间及自发活动的影响.方法 按药物分0.9%氯化钠注射液(NS)和ESZ 2个水平及按海拔分800 m、3500 m和6000 m水平的2×3析因实验设计,将120只小鼠随机分为6组,进行戊巴比妥钠睡眠时间实验和旷场实验.结果 (1)析因分析表明,药物和海拔对戊巴比妥钠睡眠时间实验和旷场实验的结果均无交互作用(P>0.05).(2)800 m、3500 m、6000 m海拔下ESZ组戊巴比妥钠睡眠时间分别为(37.77± 18,22) min,(37.02±13.67) min,(95.67±47.68) min,NS组戊巴比妥钠睡眠时间分别为(17.78± 14.10) min,(15.09± 12.46) min,(39.54±28.24) min,ESZ组睡眠时间均较相应海拔的NS组延长(P<0.05);6000 m海拔的ESZ组和NS组均较800 m和3500 m海拔相应用药组延长(P<0.05).(3)旷场实验显示,相同海拔NS与ESZ组间比较差异无统计学意义(P>0.05);6000m海拔NS组和ESZ组小鼠用药6h后自发活动较800 m海拔相应用药组减少(P<0.05).结论 ESZ延长低压低氧小鼠戊巴比妥钠睡眠时间,且6000 m海拔条件下效果最明显.但不影响用药6h后小鼠自发活动;6000 m海拔低压低氧延长戊巴比妥钠睡眠时间,减少小鼠自发活动.%Objective To assess the effects of eszopiclone (ESZ) on the pentobarbital sodium-induced sleeping time and spontaneous activity in mice exposed to acute hypobaric hypoxia.Methods 120 mice were randomly divided into 6 groups by using two factors 2×3 levels factorial design,in which two factors were interventions (ESZ and 0.9% sodium chloride,2 levels) and altitudes (800 m,3500 m and 6000 m,3 levels).The pentobarbital sodium-induced sleeping test and the open field test were engaged to assess the effects of ESZ on sleeping time and spontaneous activity.Results (1) The drug and altitude had no interaction in the results of both the pentobarbital sodium-induced sleeping test and the open field test(P>0

  1. Heat acclimation attenuates physiological strain and the HSP72, but not HSP90 alpha, mRNA response to acute normobaric hypoxia

    OpenAIRE

    Gibson, OR; Turner, G.; Tuttle, JA; Taylor, L.; Watt, PW; Maxwell, NS

    2015-01-01

    Heat acclimation (HA) attenuates physiological strain in hot conditions via phenotypic and cellular adaptation. The aim of this study was to determine whether HA reduced physiological strain, and heat shock protein (HSP) 72 and HSP90α mRNA responses in acute normobaric hypoxia. Sixteen male participants completed ten 90-min sessions of isothermic HA (40°C/40% relative humidity) or exercise training [control (CON); 20°C/40% relative humidity]. HA or CON were preceded (HYP1) and proceeded (HYP2...

  2. 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.

  3. 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. PMID:27688788

  4. 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.

  5. 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

  6. 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

  7. Gene Therapy by Targeted Adenovirus-mediated Knockdown of Pulmonary Endothelial Tph1 Attenuates Hypoxia-induced Pulmonary Hypertension

    OpenAIRE

    Morecroft, Ian; White, Katie; Caruso, Paola; Nilsen, Margaret; Loughlin, Lynn; Alba, Raul; Reynolds, Paul N; Danilov, Sergei M.; Andrew H. Baker; MacLean, Margaret R.

    2012-01-01

    Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of a gene therapy approach to PAH using selective inhibition of PAEC-Tph1 in vivo in a hypoxic model of PAH. We exposed cultured bovine pulmo...

  8. Overexpression of DJ-1 reduces oxidative stress and attenuates hypoxia/reoxygenation injury in NRK-52E cells exposed to high glucose

    Science.gov (United States)

    Shen, Zi-Ying; Sun, Qian; Xia, Zhong-Yuan; Meng, Qing-Tao; Lei, Shao-Qing; Zhao, Bo; Tang, Ling-Hua; Xue, Rui; Chen, Rong

    2016-01-01

    Patients with diabetes are more vulnerable to renal ischemia/reperfusion (I/R) injury, which is implicated in hyperglycemia-induced oxidative stress. We previously reported that the hyperglycemia-induced inhibition of DJ-1, a novel oncogene that exhibits potent antioxidant activity, is implicated in the severity of myocardial I/R injury. In the present study, we aimed to explore the role of DJ-1 in hypoxia/reoxygenation (H/R) injury in renal cells exposed to high glucose (HG). For this purpose, NRK-52E cells were exposed to HG (30 mM) for 48 h and then exposed to hypoxia for 4 h and reoxygenation for 2 h, which significantly decreased cell viability and superoxide dismutase (SOD) activity, and increased the malondialdehyde (MDA) content, accompanied by a decrease in DJ-1 protein expression. The overexpression of DJ-1 by transfection with a DJ-1 overexpression plasmid exerted protective effects against HG-induced H/R injury, as evidenced by increased CCK-8 levels and SOD activity, the decreased release of lactate dehydrogenase (LDH) and the decreased MDA content, and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Similar effects were observed following treatment with the antioxidant, N-acetylcysteine. These results suggest that the overexpression of DJ-1 reduces oxidative stress and attenuates H/R injury in NRK-52E cells exposed to HG. PMID:27430285

  9. 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.

  10. Cerebral Hypoxia

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  11. 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.

  12. 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.

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

    Science.gov (United States)

    Bobyleva, Polina I.; Andreeva, Elena R.; Gornostaeva, Aleksandra N.; Buravkova, Ludmila B.

    2016-01-01

    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. PMID:26880965

  14. 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.

  15. 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. PMID:18160846

  16. Germination under Extreme Hypobaric and Hypoxic Environment

    Science.gov (United States)

    Hashimoto, Hirofumi

    Is the agriculture on Mars without a pressured greenhouse dome possible? In order to inves-tigate a possibility of plant cultivation for the space agriculture on Mars, germination rate for six species of plant, Jute, Chrysanthemum, Komatsuna, Cucumber, Okra, and Eggplant under extreme hypobaric and hypoxic condition was measured. Oxygen partial pressure was 1kPa which was equal to 1/100 of normal earth atmosphere. Seeds of Jute and Cucumber were able to germinate in six species. In the case of Jute, germination rate under the oxygen partial pressure of 1kPa was very high, 70

  17. Clematichinenoside (AR Attenuates Hypoxia/Reoxygenation-Induced H9c2 Cardiomyocyte Apoptosis via a Mitochondria-Mediated Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Haiyan Ding

    2016-05-01

    Full Text Available Mitochondria-mediated cardiomyocyte apoptosis is involved in myocardial ischemia/reperfusion (MI/R injury. Clematichinenoside (AR is a triterpenoid saponin isolated from the roots of Clematis chinensis with antioxidant and anti-inflammatory cardioprotection effects against MI/R injury, yet the anti-apoptotic effect and underlying mechanisms of AR in MI/R injury remain unclear. We hypothesize that AR may improve mitochondrial function to inhibit MI/R-induced cardiomyocyte apoptosis. In this study, we replicated an in vitro H9c2 cardiomyocyte MI/R model by hypoxia/reoxygenation (H/R treatment. The viability of H9c2 cardiomyocytes was determined by MTT assay; apoptosis was evaluated by flow cytometry and TUNEL experiments; mitochondrial permeability transition pore (mPTP opening was analyzed by a calcein-cobalt quenching method; and mitochondrial membrane potential (ΔΨm was detected by JC-1. Moreover, we used western blots to determine the mitochondrial cytochrome c translocation to cytosolic and the expression of caspase-3, Bcl-2, and Bax proteins. These results showed that the application of AR decreased the ratio of apoptosis and the extent of mPTP opening, but increased ΔΨm. AR also inhibited H/R-induced release of mitochondrial cytochrome c and decreased the expression of the caspase-3, Bax proteins. Conversely, it remarkably increased the expression of Bcl-2 protein. Taken together, these results revealed that AR protects H9c2 cardiomyocytes against H/R-induced apoptosis through mitochondrial-mediated apoptotic signaling pathway.

  18. Clematichinenoside (AR) Attenuates Hypoxia/Reoxygenation-Induced H9c2 Cardiomyocyte Apoptosis via a Mitochondria-Mediated Signaling Pathway.

    Science.gov (United States)

    Ding, Haiyan; Han, Rong; Chen, Xueshan; Fang, Weirong; Liu, Meng; Wang, Xuemei; Wei, Qin; Kodithuwakku, Nandani Darshika; Li, Yunman

    2016-01-01

    Mitochondria-mediated cardiomyocyte apoptosis is involved in myocardial ischemia/reperfusion (MI/R) injury. Clematichinenoside (AR) is a triterpenoid saponin isolated from the roots of Clematis chinensis with antioxidant and anti-inflammatory cardioprotection effects against MI/R injury, yet the anti-apoptotic effect and underlying mechanisms of AR in MI/R injury remain unclear. We hypothesize that AR may improve mitochondrial function to inhibit MI/R-induced cardiomyocyte apoptosis. In this study, we replicated an in vitro H9c2 cardiomyocyte MI/R model by hypoxia/reoxygenation (H/R) treatment. The viability of H9c2 cardiomyocytes was determined by MTT assay; apoptosis was evaluated by flow cytometry and TUNEL experiments; mitochondrial permeability transition pore (mPTP) opening was analyzed by a calcein-cobalt quenching method; and mitochondrial membrane potential (ΔΨm) was detected by JC-1. Moreover, we used western blots to determine the mitochondrial cytochrome c translocation to cytosolic and the expression of caspase-3, Bcl-2, and Bax proteins. These results showed that the application of AR decreased the ratio of apoptosis and the extent of mPTP opening, but increased ΔΨm. AR also inhibited H/R-induced release of mitochondrial cytochrome c and decreased the expression of the caspase-3, Bax proteins. Conversely, it remarkably increased the expression of Bcl-2 protein. Taken together, these results revealed that AR protects H9c2 cardiomyocytes against H/R-induced apoptosis through mitochondrial-mediated apoptotic signaling pathway. PMID:27248986

  19. 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...

  20. Short-term supplementation with alpha-ketoglutaric acid and 5-hydroxymethylfurfural does not prevent the hypoxia induced decrease of exercise performance despite attenuation of oxidative stress.

    Science.gov (United States)

    Gatterer, H; Greilberger, J; Philippe, M; Faulhaber, M; Djukic, R; Burtscher, M

    2013-01-01

    Reactive oxygen species are thought to partly be responsible for the hypoxia induced performance decrease. The present study evaluated the effects of a broad based antioxidant supplementation or the combined intake of alpha-ketoglutaric acid (α-KG) and 5-hydroxymethylfurfural (5-HMF) on the performance decrease at altitude. 18 healthy, well-trained males (age: 25±3 years; height: 179±6 cm; weight: 76.4±6.8 kg) were randomly assigned in a double-blind fashion to a placebo group (PL), a α-KG and 5-HMF supplementation group (AO1) or a broad based antioxidant supplementation group (AO2). Participants performed 2 incremental exercise tests to exhaustion on a cycle ergometer; the first test under normoxia and the second under hypoxia conditions (simulated altitude, FiO2=13% ~ 4 300 m). Supplementation started 48 h before the hypoxia test. Maximal oxygen uptake, maximal power output, power output at the ventilatory and lactate threshold and the tissue oxygenation index (NIRS) were measured under both conditions. Oxidative stress markers were measured before the supplementation and after the hypoxia test. Under hypoxia conditions all performance parameters decreased in the range of 19-39% with no differences between groups. A significant change from normoxia to hypoxia (pextraction, as indicated by the tissue oxygenation index, might indicate that mitochondrial functioning was actually influenced by the supplementation. PMID:22893323

  1. 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.

  2. Re-exposure to the hypobaric hypoxic brain injury of high altitude: plasma S100B levels and the possible effect of acclimatisation on blood-brain barrier dysfunction.

    Science.gov (United States)

    Winter, C D; Whyte, T; Cardinal, J; Kenny, R; Ballard, E

    2016-04-01

    Hypobaric hypoxic brain injury results in elevated peripheral S100B levels which may relate to blood-brain barrier (BBB) dysfunction. A period of acclimatisation or dexamethasone prevents altitude-related illnesses and this may involve attenuation of BBB compromise. We hypothesised that both treatments would diminish the S100B response (a measure of BBB dysfunction) on re-ascent to the hypobaric hypoxia of high altitude, in comparison to an identical ascent completed 48 h earlier by the same group. Twelve healthy volunteers, six of which were prescribed dexamethasone, ascended Mt Fuji (summit 3700 m) and serial plasma S100B levels measured. The S100B values reduced from a baseline 0.183 µg/l (95 % CI 0.083-0.283) to 0.145 µg/l (95 % CI 0.088-0.202) at high altitude for the dexamethasone group (n = 6) and from 0.147 µg/l (95 % CI 0.022-0.272) to 0.133 µg/l (95 % CI 0.085-0.182) for the non-treated group (n = 6) [not statistically significant (p = 0.43 and p = 0.82) for the treated and non-treated groups respectively]. [These results contrasted with the statistically significant increase during the first ascent, S100B increasing from 0.108 µg/l (95 % CI 0.092-0.125) to 0.216 µg/l (95 % CI 0.165-0.267) at high altitude]. In conclusion, an increase in plasma S100B was not observed in the second ascent and this may relate to the effect of acclimatisation (or hypoxic pre-conditioning) on the BBB. An exercise stimulated elevation of plasma S100B levels was also not observed during the second ascent. The small sample size and wide confidence intervals, however, precludes any statistically significant conclusions and a larger study would be required to confirm these findings. PMID:26924650

  3. CPU86017-RS attenuated hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines

    Institute of Scientific and Technical Information of China (English)

    Guo-lin ZHANG; Feng YU; De-zai DAI; Yu-si CHENG; Can ZHANG; Yin DAI

    2012-01-01

    Aim:Downregulation of androgen biosynthesis genes StAR (steroidogenic acute regulatory)and 3β-HSD (3β-hydroxysteroid dehydrogenase)contributes to low testosterone levels in hypoxic mice and is possibly related to increased expression of pro-inflammatory cytokines in the testis.The aim of this study is to investigate the effects of CPU86017-RS that block Ca2+ influx on hypoxia-induced testis insult in mice.Methods:Male ICR mice were divided into 5 groups:control group,hypoxia group,hypoxia group treated with nifedipine (10 mg/kg),hypoxia groups treated with CPU86017-RS (60 or 80 mg/kg).Hypoxia was induced by placing the mice in a chamber under 10%+0.5% 02 for 28 d (8 h per day).The mice were orally administered with drug in the last 14 d.At the end of experiment the testes of the mice were harvested.The mRNA and protein levels of StAR,3β-HSD,connexin 43 (Cx43),matrix metalloprotease 9 (MMP9),endothelin receptor A (ETAR)and leptin receptor (OBRb)were analyzed using RT-PCR and Western blotting,respectively.The malondialdehyde (MDA),lactate dehydrogenase (LDH),succinate dehydrogenase (SDH)and acid phosphatase (ACP)levels were measured using biochemical kits.Serum testosterone concentration was measured with radioimmunoassay.Results:Hypoxia significantly increased the MDA level,and decreased the LDH,ACP and SDH activities in testes.Meanwhile,hypoxia induced significant downregulation of StAR and 3β-HSD in testes responsible for reduced testosterone biosynthesis.It decreased the expression of Cx43,and increased the expression of MMP9,ETAR and OBRb,leading to abnormal testis function and structure.These changes were effectively diminished by CPU86017-RS (80 mg/kg)or nifedipine (10 mg/kg).Conclusion:Low plasma testosterone level caused by hypoxia was due to downregulation of StAR and 3β-HSD genes,in association with an increased expression of pro-inflammatory cytokines.These changes can be alleviated by CPU86017-RS or nifedipine.

  4. 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...

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

    OpenAIRE

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

    2013-01-01

    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 cell...

  6. 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.

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

    International Nuclear Information System (INIS)

    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 CoCl2 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

  8. 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 < 0.001, Mann-Whitney t-test), thus inducing cellular resistance towards 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. PMID:24330097

  9. Cerebral hypoxia

    Science.gov (United States)

    ... the veins ( deep vein thrombosis ) Lung infections (pneumonia) Malnutrition When to Contact a Medical Professional Cerebral hypoxia ... References Bernat JL. Coma, vegetative state, and brain death. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

  10. [Exercise training in hypoxia prevents hypoxia induced mitochondrial DNA oxidative damage in skeletal muscle].

    Science.gov (United States)

    Bo, Hai; Li, Ling; Duan, Fu-Qiang; Zhu, Jiang

    2014-10-25

    This study was undertaken to investigate the effect of exercise training on mitochondrial DNA (mtDNA) oxidative damage and 8-oxoguanine DNA glycosylase-1 (OGG1) expression in skeletal muscle of rats under continuous exposure to hypoxia. Male Sprague-Dawley rats were randomly divided into 4 groups (n = 8): normoxia control group (NC), normoxia training group (NT), hypoxia control group (HC), and hypoxia training group (HT). The hypoxia-treated animals were housed in normobaric hypoxic tent containing 11.3% oxygen for consecutive 4 weeks. The exercise-trained animals were exercised on a motor-driven rodent treadmill at a speed of 15 m/min, 5% grade for 60 min/day, 5 days per week for 4 weeks. The results showed that, compared with NC group, hypoxia attenuated complex I, II, IV and ATP synthase activities of the electron transport chain, and the level of mitochondrial membrane potential in HC group (P hypoxia decreased mitochondrial OGG1, MnSOD, and GPx activities (P hypoxia attenuated muscle and mitochondrial [NAD⁺]/ [NADH] ratio, and SIRT3 protein expression (P exercise training in hypoxia elevated complex I, II, IV and ATP synthase activities, and the level of mitochondrial membrane potential in HT group (P exercise training in hypoxia increased MnSOD and GPx activities and mitochondrial OGG1 level (P exercise training in hypoxia increased muscle and mitochondrial [NAD⁺]/[NADH] ratio, as well as SIRT3 protein expression (P exercise training in hypoxia can decrease hypoxia-induced mtDNA oxidative damage in the skeletal muscle through up-regulating exercise-induced mitochondrial OGG1 and antioxidant enzymes. Exercise training in hypoxia may improve hypoxia tolerance in skeletal muscle mitochondria via elevating [NAD⁺]/[NADH] ratio and SIRT3 expression. PMID:25332006

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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

  13. Effect of Hypoxia and Bedrest on Peripheral Vasoconstriction

    Science.gov (United States)

    McDonnell, Adam C.; Mekjavic, Igor B.; Dolenc-Groselj, Leja; Jaki Mekjavic, Polona; Eiken, Ola

    2013-02-01

    Future planetary habitats may expose astronauts to both microgravity and hypobaric hypoxia, both inducing a reduction in peripheral perfusion. Peripheral temperature changes have been linked to sleep onset and quality [5]. However, it is still unknown what effect combining hypoxia and bedrest has on this relationship. Eleven male participants underwent three 10-day campaigns in a randomized manner: 1) normobaric hypoxic ambulatory confinement (HAmb); 2) normobaric hypoxic bed rest (HBR); 3) normobaric normoxic bed rest (NBR). There was no change in skin temperature gradient between the calf and toes, an index of peripheral perfusion (Δ Tc-t), over the 10-d period in the HAmb trial. However, there was a significant increase (preduction in the perfusion of the toes during the daytime was augmented during the HBR trial compared to NBR (psleep onset and/or architecture. These data support the theory that circadian changes in temperature are functionally linked to sleepiness [1].

  14. 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.

  15. Carbon dioxide exchange of lettuce plants under hypobaric conditions

    Science.gov (United States)

    Corey, K. A.; Bates, M. E.; Adams, S. L.; MacElroy, R. D. (Principal Investigator)

    1996-01-01

    Growth of plants in a Controlled Ecological Life Support System (CELSS) may involve the use of hypobaric pressures enabling lower mass requirements for atmospheres and possible enhancement of crop productivity. A controlled environment plant growth chamber with hypobaric capability designed and built at Ames Research Center was used to determine if reduced pressures influence the rates of photosynthesis (Ps) and dark respiration (DR) of hydroponically grown lettuce plants. The chamber, referred to as a plant volatiles chamber (PVC), has a growing area of about 0.2 m2, a total gas volume of about 0.7 m3, and a leak rate at 50 kPa of CO2 than at 81 Pa CO2. This is consistent with reports showing greater inhibition of photorespiration (Pr) in reduced O2 at low CO2 concentrations. When the partial pressure of O2 was held constant but the total pressure was varied between 51 and 101 kPa, the rate of CO2 uptake was nearly constant, suggesting that low pressure enhancement of Ps may be mainly attributable to lowered partial pressure of O2 and the accompanying reduction in Pr. The effects of lowered partial pressure of O2 on Ps and DR could result in substantial increases in the rates of biomass production, enabling rapid throughput of crops or allowing flexibility in the use of mass and energy resources for a CELSS.

  16. 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.

  17. 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...

  18. Determinants of erythropoietin release in response to short-term hypobaric hypoxia

    Science.gov (United States)

    Ge, Ri-Li; Witkowski, S.; Zhang, Y.; Alfrey, C.; Sivieri, M.; Karlsen, T.; Resaland, G. K.; Harber, M.; Stray-Gundersen, J.; Levine, B. D.

    2002-01-01

    We measured blood erythropoietin (EPO) concentration, arterial O(2) saturation (Sa(O(2))), and urine PO(2) in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood flow (Doppler) and Hb were determined at sea level and after 6 h at each altitude (n = 24) to calculate renal O(2) delivery. EPO increased significantly after 6 h at all altitudes and continued to increase after 24 h at 2,454 and 2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied markedly among individuals, ranging from -41 to 400% after 24 h at 2,800 m. Similar to EPO, urine PO(2) decreased after 6 h at all altitudes and returned to baseline by 24 h at the two lowest altitudes but remained decreased at the two highest altitudes. Urine PO(2) was closely related to EPO via a curvilinear relationship (r(2) = 0.99), although also with prominent individual variability. Renal blood flow remained unchanged at all altitudes. Sa(O(2)) decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit statistically significant, relationships between EPO and Sa(O(2)) (r = 0.41, P or =2,100-2,500 m appear to be a threshold for stimulating sustained EPO release in most subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in the erythropoietic response to altitude that is only partially explained by "upstream" physiological factors such as those reflecting O(2) delivery to EPO-producing tissues.

  19. Influence of experimental hypoxia on the content of toxic and trace microelements in the tissues of newborn rats

    Directory of Open Access Journals (Sweden)

    Tarasova I.

    2011-01-01

    Full Text Available Organs of newborn rats (cerebrum, heart, liver, kidneys are characterized by a high contains of microelements. Review of toxic and ultramikroelements in the tissues of vital organs in case of severity is essential for understanding hypoxic-ischemic lesions in neonatology. In this paper we used hypobaric model of hypoxia, the study conducted on 60 laboratory rats for the first and seventh day of life. By the seventh day of life the content of chrome and manganese decreases. In cerebrum contain of lead is the most. Hypoxia leads to a considerable decrease of the level of manganese. Severe hypoxia leads to the decrease of contain of chrome and cobalt. Hypoxia causes increase of accumulation of lead in heart and kidneys in 8 times, in liver – in 3 times, and also in cerebrum (28, 2%.

  20. Hypoxia. 2. Hypoxia regulates cellular metabolism

    OpenAIRE

    Wheaton, William W.; Chandel, Navdeep S.

    2010-01-01

    Adaptation to lowering oxygen levels (hypoxia) requires coordinated downregulation of metabolic demand and supply to prevent a mismatch in ATP utilization and production that might culminate in a bioenergetic collapse. Hypoxia diminishes ATP utilization by downregulating protein translation and the activity of the Na-K-ATPase. Hypoxia diminishes ATP production in part by lowering the activity of the electron transport chain through activation of the transcription factor hypoxia-inducible fact...

  1. Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia

    OpenAIRE

    Song, Ting-Ting; Bi, Yan-Hua; Gao, Yu-Qi; Huang, Rui; Hao, Ke; Xu, Gang; Tang, Jia-Wei; Ma, Zhi-qiang; Kong, Fan-Ping; Coote, John H.; Chen, Xue-qun; Du, Ji-Zeng

    2016-01-01

    Background High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness (AMS) and life threatening. A subclinical inflammation has been speculated, but the exact mechanisms underlying the HACE are not fully understood. Methods Human volunteers ascended to high altitude (3860 m, 2 days), and rats were exposed to hypoxia in a hypobaric chamber (5000 m, 2 days). Human acute mountain sickness was evaluated by the Lake Louise Score (LLS), and plasma corticotrophin-releasing ho...

  2. 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.

  3. The study of genistein attenuating genioglossus muscle fatigue under chronic intermittent hypoxia%金雀异黄素减弱慢性间歇性低氧大鼠颏舌肌疲劳的实验研究

    Institute of Scientific and Technical Information of China (English)

    丁王辉; 李文; 陈小燕; 施洁珺

    2016-01-01

    weeks.Electrophysiological method was used to detect the change of genioglossus muscle function, and real-time reverse transcription(RT)-PCR and Western blotting were used to determine the level of Nrf-2 gene and protein.Results Compared to NC group, the contractive properties of genioglossus muscle fatigue test at every time set was significantly decreased in CIH group(P<0.05).Compared to CIH group, the contractive properties was significantly increased in T group(P<0.05).The level of Nrf-2 gene and protein were less in CIH group(0.54±0.11 and 0.35±0.13) than in NC group(1.00±0.00 和 1.00±0.00)(P<0.05).Compared to CIH group the level of Nrf-2 gene and protein were increased in T group (0.76 ± 0.16 and 0.63 ± 0.14)(P<0.05), however, it was still less than the level in NC group(P<0.05).Conclusions CIH attenuates genioglossus muscle fatigue resistance under chronic intermittent hypoxia through Nrf-2/ARE signaling pathway.Genistein protects genioglossus muscle function through up-regulation of the level of Nrf-2 gene and protein.

  4. Suppression of TRPV4 channels ameliorates anti-dipsogenic effects under hypoxia in the subfornical organ of rats.

    Science.gov (United States)

    Yang, Fan; Zhou, Li; Wang, Dong; Yang, Li-Li; Yuan, Guo-Rong; Huang, Qing-Yuan

    2016-01-01

    The phenomenon of water intake reduction during the 1(st) day of hypobaric hypoxia has been known for a long time. However, the reason for the same is yet unknown. The transient receptor potential vanilloid (TRPV) channels, including TRPV1 and TRPV4, are located in the subfornical organ (SFO). These are calcium permeable cationic channels gated by various stimuli such as cell swelling, low pH, and high temperature, and participate in anti-dipsogenic effects when activated. We aimed to explore the drinking behavior of rats and the mechanism of TRPVs under hypoxia. Chemical TRPV4 inhibitors (HC-067047 and Gadolinium) or TRPV4 knockout, but not TRPV1 inhibitor SB-705498, could restore the water intake under hypoxia. Hypoxia-mediated direct activation of TRPV4 may be the reason of anti-dipsogenic effects because the serum sodium, pH, and intracranial temperature are unaltered. Interestingly, we found that hypoxia immediately increased the intracellular Ca(2+) concentration ([Ca(2+)]i) in HEK293-TRPV4 cells and primary neurons from SFO region, but not in the HEK293-TRPV1 cells. Moreover, hypoxia-induced [Ca(2+)]i increase depended on the indispensable hemeoxygenase-2 (HO-2) and TRPV4. HO-2 and TRPV4 were also confirmed to form a complex in SFO neurons. These results demonstrated that SFO cells sense hypoxia and activate via the HO-2/TRPV4 multiple channels, which are associated with anti-dipsogenic effects. PMID:27436489

  5. Hypoxia, MTOR and autophagy

    OpenAIRE

    Blagosklonny, Mikhail V.

    2013-01-01

    Although hypoxia can cause cell cycle arrest, it may simultaneously suppress a conversion from this arrest to senescence. Furthermore, hypoxia can suppress senescence caused by diverse stimuli, maintaining reversible quiescence instead. Hypoxia activates autophagy and inhibits MTOR, thus also activating autophagy. What is the relationship between autophagy and cellular senescence? Also, can inhibition of MTOR and stimulation of autophagy explain the gerosuppressive effects of hypoxia?

  6. Effects of hypoxia on interval moderate exercise

    Directory of Open Access Journals (Sweden)

    TASOS ADAMOS, ZISIS PAPANIKOLAOU, VASILIOS VOUTSELAS,DIMITRIOS SOULAS

    2008-01-01

    Full Text Available There is a controversy in the published scientific data whether extended training at altitude increases performance at sea level. The effect of hypoxia at rest and on the response to interval moderate exercise was determined in six healthy male individuals during an incremental 3×5min exercise cycle test (5min recovery at sea level and in a hypobaric chamber (10000 feet/3100m altitude. Ventilation rate (VE, breathing frequency (BF, heart rate (HR, cardiac output (Q, blood lactate (Labl and % of arterial oxygen saturation (SaO2 were measured. Blood samples were drawn at rest and at the end of each exercise bout. Hypoxia led to a significant increase in VE during exercise (81.7 vs. 62, 87 vs. 66, 89 vs. 64ml/l, for the three exercise bouts, respectively p<.05. There was also a significant increase in BF (11.3 vs. 10, 29 vs. 25, 32 vs. 24, 33 vs. 25, p<.05, HR (73 vs. 62, 153 vs. 138, 161 vs. 138, 166 vs. 137b/min, p<.05, Q (4.8 vs. 4, 13.1 vs. 12.5, 14.6 vs. 12.2, 15.5 vs. 12.8l/min, p<.05 and Labl (0.41 vs. 0.35, 3.8 vs. 2.6, 4.7 vs 3, 5.9 vs 2.9 mmol/l, p<.05 at rest and during exercise. Hypoxia lowered SaO2 at rest and exercise (99.3 vs 98.6, 98.1 vs 95.1, 98.5 vs 95.3, 98.3 vs 95.5%, p<.05. The results suggest that there is a hypoxic augmentation of the cardiorespiratory variables measured. Also we concluded that exercise potentiated the acute ventilatory response to hypoxia by increasing VE, breathing frequency, heart rate, cardiac output, blood lactate and decreasing SaO2.

  7. Effect of intermittent hypoxia and exercise on blood rheology and oxygen transport in trained rats.

    Science.gov (United States)

    Núñez-Espinosa, Cristian; Douziech, Anne; Ríos-Kristjánsson, Juan Gabriel; Rizo, David; Torrella, Joan Ramon; Pagès, Teresa; Viscor, Ginés

    2014-02-01

    Intermittent hypobaric hypoxia (IHH) exposure, accompanied or not with active recovery, can help to skeletal muscle repair. However, the erythropoietic response elicited can disturb blood rheology and thus alter the oxygen delivery to tissues. Male Sprague-Dawley rats were studied in two basal states: untrained and trained and compared with early (1-3 days) and late (7-14 days) stages of damage recovery in three groups of trained rats that had suffered skeletal muscle injury: Control, passive recovery rats; HYP, rats exposed to IHH after muscle damage; and EHYP, trained rats that performed light aerobic exercise sessions in addition to IHH. Hematocrit, RBC count and hemoglobin were only elevated in the late stage of recovery in HYP (13%; 14% and 8%) and EHYP (18%; 13% and 15%) groups. Blood viscosity increased about double for EHYP rats. It is concluded that intermittent exposure to hypobaric hypoxia in combination with light aerobic exercise in normoxia has an erythropoietic effect, but also provides advantageous hemorheological conditions for the perfusion of damaged muscle. PMID:24373840

  8. Exploiting Aerobic Fitness to Reduce Risk of Hypobaric Decompression Sickness

    Science.gov (United States)

    Conkin, J.; Gernhardt, M. L.; Wessel, J. H.

    2007-01-01

    Decompression sickness (DCS) is multivariable. But we hypothesize an aerobically fit person is less likely to experience hypobaric DCS than an unfit person given that fitness is exploited as part of the denitrogenation (prebreathe, PB) process prior to an altitude exposure. Aerobic fitness is peak oxygen uptake (VO2pk, ml/kg/min). Treadmill or cycle protocols were used over 15 years to determine VO2pks. We evaluated dichotomous DCS outcome and venous gas emboli (VGE) outcome detected in the pulmonary artery with Doppler ultrasound associated with VO2pk for two classes of experiments: 1) those with no PB or PB under resting conditions prior to ascent in an altitude chamber, and 2) PB that included exercise for some part of the PB. There were 165 exposures (mean VO2pk 40.5 plus or minus 7.6 SD) with 25 cases of DCS in the first protocol class and 172 exposures (mean VO2pk 41.4 plus or minus 7.2 SD) with 25 cases of DCS in the second. Similar incidence of the DCS (15.2% vs. 14.5%) and VGE (45.5% vs. 44.8%) between the two classes indicates that decompression stress was similar. The strength of association between outcome and VO2pk was evaluated using univariate logistic regression. An inverse relationship between the DCS outcome and VO2pk was evident, but the relationship was strongest when exercise was done as part of the PB (exercise PB, coef. = -0.058, p = 0.07; rest or no PB, coef. = -0.005, p = 0.86). There was no relationship between VGE outcome and VO2pk (exercise PB, coef. = -0.003, p = 0.89; rest or no PB, coef. = 0.014, p = 0.50). A significant change in probability of DCS was associated with fitness only when exercise was included in the denitrogenation process. We believe a fit person that exercises during PB efficiently eliminates dissolved nitrogen from tissues.

  9. 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.

  10. 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...

  11. Sildenafil does not Improve Exercise Capacity under Acute Hypoxia Exposure.

    Science.gov (United States)

    Toro-Salinas, A H; Fort, N; Torrella, J R; Pagès, T; Javierre, C; Viscor, G

    2016-09-01

    The increase in pulmonary arterial pressure (PAP) due to hypoxic pulmonary vasoconstriction (HPV) could be a limiting factor for physical performance during hypoxic exposure. Sildenafil has been shown to reduce PAP in situations of moderate or severe hypoxia, and consequently its role as an ergogenic aid and even a possible doping substance must be considered. We performed a double-blind crossover study to determine the effects of sildenafil on cardiovascular, respiratory and metabolic parameters in normoxia and during acute exposure to hypobaric hypoxia (4 000 m) at rest and during maximal and submaximal (60% VO2 max) exercise tests. One hour before testing started, sildenafil (100 mg) or a placebo was orally administered to 11 volunteers. In normoxic conditions, sildenafil did not affect performance. Similarly, no significant differences were found in cardiovascular and respiratory parameters in hypoxic conditions at rest or during exercise. The use of sildenafil to improve physical performance in non-acclimatized subjects is not supported by our data. PMID:27414159

  12. [DYNAMICS OF GLUTAMINE SYNTHASE ACTIVITY IN RAT BRAIN IN PRENATAL HYPOXIA MODEL].

    Science.gov (United States)

    Khairova, V R; Safarov, M I

    2015-01-01

    Prenatal ontogenesis is a period of high sensitivity to stressful impact, so any stressor can lead to changes of physiological, biochemical indicators, behavioral and cognitive functions. The most common and clinically significant stress factor, which the embryo may be exposed during embryonic development, is hypoxia. In this case pathological changes in the central nervous system depend on the duration and severity of hypoxic exposure, individual tolerance and the stage of prenatal development, at each of which in the brain take place the basic histogenetic processes. By activating energetically disadvantageous anaerobic glycolysis hypoxia leads to excess of glutamate emission and cell apoptosis. Glutamine synthase is a basic enzyme that regulates metabolism of glutamate, catalyzing conversion of glutamate to glutamine with ammonia detoxification. The aim of the presented work was to reveal changes in the activity of one of the key enzyme of glutamate metabolism- glutamine synthetase in the brain of offspring of white rats undergone to hypoxia at different stages of prenatal ontogenesis. Hypoxia was created by placing female rats at stages of the pregnancy, corresponding to progestation period of organogenesis and fetal period of prenatal development, in the hypobaric chamber with exposure to 5% oxygen and 95% nitrogen gas mixture during 30 minutes per day. The offspring obtained from females of control and experimental groups were used for biochemical determinations in the age of 1 and 3 month. It has been established that hypoxia exposed to pregnant females during embryonic organogenesis causes significant changes in enzyme activity, particularly pronounced in the cerebral cortex and cerebellum, as compared with progestational and fetal hypoxia. Enzyme activity decreased in a greater degree in one-month-old rats undergone to prenatal hypoxia, than three- month-old animals. Thus, stress during intensive processes of proliferation and migration of cells of the

  13. 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...

  14. Sustained acclimatization in Chilean mine workers subjected to chronic intermittent hypoxia.

    Science.gov (United States)

    Farias, Jorge G; Osorio, Jorge; Soto, Gustavo; Brito, Julio; Siques, Patricia; Reyes, Juan G

    2006-01-01

    Farias, Jorge G., Jorge Osorio, Gustavo Soto, Julio Brito, Patricia Siques, and Juan G. Reyes. Sustained acclimatization in Chilean mine workers subjected to chronic intermittent hypoxia. High Alt. Med. Biol. 7:302-306, 2006--We wanted to know if sea-level mine workers exposed previously to chronic intermittent hypoxia reached a steady acclimatization at 36 months under hypobaric hypoxia. An intermittently exposed group of mine workers (IE, n = 25) were subjected to submaximal exercise (100 W) at 4500 m. Their systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and hemoglobin oxygen saturation (HbSatO(2)) were monitored. Two comparison groups of unacclimatized sea-level workers (n = 17) were studied. A nonexposed group (NE) performed 5 min of submaximal exercise at sea level. Some kind of exercise was performed both by an acutely exposed group (AE) and IE group at 4500 m. No statistical differences were found for HR, SBP, and DBP (p > 0.05) during exercise between IE and AE groups. Resting HbSatO(2) of IE (87 +/- 6%) was lower than NE (97 +/- 3%) (p < 0.05), but was higher than AE (82 +/- 4%) (p < 0.05). In the exercise condition, HbSatO(2) of IE (85 +/- 5%) was lower than NE (95 +/- 3%) (p < 0.05), but was higher than AE (76 +/- 2%) (p < 0.05). These responses were maintained through the 6 months of the study period. Thus, mine workers subjected to intermittent hypobaric condition for 3 years showed a good degree of acclimatization that was maintained through time. PMID:17173515

  15. Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress.

    Science.gov (United States)

    Farías, Jorge G; Herrera, Emilio A; Carrasco-Pozo, Catalina; Sotomayor-Zárate, Ramón; Cruz, Gonzalo; Morales, Paola; Castillo, Rodrigo L

    2016-02-01

    Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies. PMID:26617218

  16. Effect of hypobaric storage on quality, antioxidant enzyme and antioxidant capability of the Chinese bayberry fruits

    OpenAIRE

    Chen, Hangjun; Yang, Hailong; Gao, Haiyan; Long, Jie; Tao, Fei; Fang, Xiangjun; Jiang, Yueming

    2013-01-01

    Background The Chinese bayberry (Myrica rubra Sieb. and Zucc.) is a subtropical fruit native to China, with unique flavor, sweet and sour taste, and high nutrition and health values. The fruit is highly perishable and susceptible to mechanical injury, physiological deterioration and fungal decay once harvested. This study was to investigate the effect of hypobaric storage on the quality of Chinese bayberry fruit and then develop storage technology to prolong the supply of the fruit. Results T...

  17. 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.

  18. 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.

  19. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation

    NARCIS (Netherlands)

    W.D. Toff; C.I. Jones; I. Ford; R.J. Pearse; H.G. Watson; S.J. Watt; J.A.S. Ross; D.P. Gradwell; A.J. Batchelor; K.R. Abrams; J.C.M. Meijers; A.H. Goodall; M. Greaves

    2006-01-01

    Context The link between long-haul air travel and venous thromboembolism is the subject of continuing debate. It remains unclear whether the reduced cabin pressure and oxygen tension in the airplane cabin create an increased risk compared with seated immobility at ground level. Objective To determin

  20. Acute Mountain Sickness, Hypoxia, Hypobaria and Exercise Duration each Affect Heart Rate.

    Science.gov (United States)

    DiPasquale, D M; Strangman, G E; Harris, N S; Muza, S R

    2015-07-01

    In this study, we quantified the changes in post-exercise resting heart rate (HRrst) associated with acute mountain sickness (AMS), and compared the effects of hypobaric hypoxia (HH) and normobaric hypoxia (NH) on HRrst. We also examined the modulating roles of exercise duration and exposure time on HRrst. Each subject participated in 2 of 6 conditions: normobaric normoxia (NN), NH, or HH (4 400 m altitude equivalent) combined with either 10 or 60 min of moderate cycling at the beginning of an 8-h exposure. AMS was associated with a 2 bpm higher HRrst than when not sick, after taking into account the ambient environment, exercise duration, and SpO2. In addition, HRrst was elevated in both NH and HH compared to NN with HRrst being 50% higher in HH than in NH. Participating in long duration exercise led to elevated resting HRs (0.8-1.4 bpm higher) compared with short exercise, while short exercise caused a progressive increase in HRrst over the exposure period in both NH and HH (0.77-1.2 bpm/h of exposure). This data suggests that AMS, NH, HH, exercise duration, time of exposure, and SpO2 have independent effects on HRrst. It further suggests that hypobaria exerts its own effect on HRrst in hypoxia. Thus NH and HH may not be interchangeable environments. PMID:25837245

  1. 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.

  2. Hypoxia in paradise: widespread hypoxia tolerance in coral reef fishes.

    OpenAIRE

    Nilsson, Göran E.; Ostlund-Nilsson, Sara

    2004-01-01

    Using respirometry, we examined the hypoxia tolerance of 31 teleost fish species (seven families) inhabiting coral reefs at a 2-5 m depth in the lagoon at Lizard Island (Great Barrier Reef, Australia). All fishes studied maintained their rate of oxygen consumption down to relatively severe hypoxia (20-30% air saturation). Indeed, most fishes appeared unaffected by hypoxia until the oxygen level fell below 10% of air saturation. This, hitherto unrecognized, hypoxia tolerance among coral reef f...

  3. Hypoxia targeting copper complexes

    International Nuclear Information System (INIS)

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

  4. Hypoxia targeting copper complexes

    Energy Technology Data Exchange (ETDEWEB)

    Dearling, J.L

    1998-11-01

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

  5. 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.

  6. 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.

  7. 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.

  8. Effects of intermittent hypoxia and light aerobic exercise on circulating stem cells and side population, after strenuous eccentric exercise in trained rats.

    Science.gov (United States)

    Núñez-Espinosa, Cristian; Ferreira, Inês; Ríos-Kristjánsson, Juan Gabriel; Rizo-Roca, David; García Godoy, Maria Dolors; Rico, Laura G; Rubi-Sans, Gerard; Torrella, Joan Ramon; Pagès, Teresa; Petriz, Jordi; Viscor, Ginés

    2015-01-01

    Our goal was to address if intermittent hypobaric hypoxia (IHH) exposure can help to increase the number of peripheral blood circulating progenitor cells and side population (SP) stem cells, in order to establish the usefulness of this intervention for skeletal muscle repair, because these cells play a role in tissue regeneration. Male Sprague-Dawley rats were studied in two basal states: untrained and trained and compared with 1, 3, 7 and 14 days stages of damage recovery of trained rats that had suffered skeletal muscle injury. Three experimental groups were studied: rats with passive recovery (CTRL); rats exposed to IHH after muscle damage (HYP); and, trained rats that, in addition to IHH, performed light aerobic exercise sessions (EHYP). We observed an increase in hematopoietic stem cells (HSCs) (mean = 0.153% of cells) and endothelial progenitor cells (EPCs) (mean = 0.0020% of cells) in EHYP on day 7. Also these cells showed characteristics of more primitive progenitors in comparison to the other experimental groups (mean = 0.107% of cells), as deduced by retention of the promising fluorescent probe Vybrant Dye Cycle Violet. We concluded that intermittent exposure to hypobaric hypoxia in combination with light aerobic exercise increased the number of HSCs and EPCs on the 7th day in EHYP group, although the exercise-induced stimulus showed a reverse effect on SP kinetics. PMID:25266982

  9. Hypoxia inhibits abdominal expiratory nerve activity.

    Science.gov (United States)

    Fregosi, R F; Knuth, S L; Ward, D K; Bartlett, D

    1987-07-01

    Our purpose was to examine the influence of steady-state changes in chemical stimuli, as well as discrete peripheral chemoreceptor stimulation, on abdominal expiratory motor activity. In decerebrate, paralyzed, vagotomized, and ventilated cats that had bilateral pneumothoraces, we recorded efferent activity from a phrenic nerve and from an abdominal nerve (cranial iliohypogastric nerve, L1). All cats showed phasic expiratory abdominal nerve discharge at normocapnia [end-tidal PCO2 38 +/- 2 Torr], but small doses (2-6 mg/kg) of pentobarbital sodium markedly depressed this activity. Hyperoxic hypercapnia consistently enhanced abdominal expiratory activity and shortened the burst duration. Isocapnic hypoxia caused inhibition of abdominal nerve discharge in 11 of 13 cats. Carotid sinus nerve denervation (3 cats) exacerbated the hypoxic depression of abdominal nerve activity and depressed phrenic motor output. Stimulation of peripheral chemoreceptors with NaCN increased abdominal nerve discharge in 7 of 10 cats, although 2 cats exhibited marked inhibition. Four cats with intact neuraxis, but anesthetized with ketamine, yielded qualitatively similar results. We conclude that when cats are subjected to steady-state chemical stimuli in isolation (no interference from proprioceptive inputs), hypercapnia potentiates, but hypoxia attenuates, abdominal expiratory nerve activity. Mechanisms to explain the selective inhibition of expiratory motor activity by hypoxia are proposed, and physiological implications are discussed. PMID:3624126

  10. 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.

  11. Hypoxia and the Presence of Human Vascular Endothelial Cells Affect Prostate Cancer Cell Invasion and Metabolism

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    Ellen Ackerstaff

    2007-12-01

    Full Text Available Tumor progression and metastasis are influenced by hypoxia, as well as by interactions between cancer cells and components of the stroma, such as endothelial cells. Here, we have used a magnetic resonance (MRcompatible invasion assay to further understand the effects of hypoxia on human prostate cancer cell invasion and metabolism in the presence and absence of human umbilical vein endothelial cells (HUVECs. Additionally, we compared endogenous activities of selected proteases related to invasion in PC-3 cells and HUVECs, profiled gene expression of PC-3 cells by microarray, evaluated cell proliferation of PC-3 cells and HUVECs by flow cytometry, under hypoxic and oxygenated conditions. The invasion of less-invasive DU-145 cells was not affected by either hypoxia or the presence of HUVECs. However, hypoxia significantly decreased the invasion of PC-3 cells. This hypoxia-induced decrease was attenuated by the presence of HUVECs, whereas under oxygenated conditions, HUVECs did not alter the invasion of PC-3 cells. Cell metabolism changed distinctly with hypoxia and invasion. The endogenous activity of selected extracellular proteases, although altered by hypoxia, did not fully explain the hypoxia-induced changes in invasion. Gene expression profiling indicated that hypoxia affects multiple cellular functions and pathways.

  12. Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade

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    Arya A

    2016-03-01

    Full Text Available Aditya Arya,1 Anamika Gangwar,1 Sushil Kumar Singh,2 Manas Roy,3,4 Mainak Das,3 Niroj Kumar Sethy,1 Kalpana Bhargava1 1Peptide and Proteomics Division, Defense Institute of Physiology and Allied Sciences, 2Functional Materials Division, Solid State Physics Laboratory, Defense Research and Development Organization, Timarpur, Delhi, 3Biological Science and Bioengineering, Indian Institute of Technology, Kanpur, 4Department of Chemistry, Indian Institute of Engineering Science and Technology, Howrah, India Abstract: Structural and functional integrity of the brain is adversely affected by reduced oxygen saturation, especially during chronic hypoxia exposure and often encountered by altitude travelers or dwellers. Hypoxia-induced generation of reactive nitrogen and oxygen species reportedly affects the cortex and hippocampus regions of the brain, promoting memory impairment and cognitive dysfunction. Cerium oxide nanoparticles (CNPs, also known as nanoceria, switch between +3 and +4 oxidation states and reportedly scavenge superoxide anions, hydrogen peroxide, and peroxynitrite in vivo. In the present study, we evaluated the neuroprotective as well as the cognition-enhancing activities of nanoceria during hypobaric hypoxia. Using polyethylene glycol-coated 3 nm nanoceria (PEG-CNPs, we have demonstrated efficient localization of PEG-CNPs in rodent brain. This resulted in significant reduction of oxidative stress and associated damage during hypoxia exposure. Morris water maze-based memory function tests revealed that PEG-CNPs ameliorated hypoxia-induced memory impairment. Using microscopic, flow cytometric, and histological studies, we also provide evidences that PEG-CNPs augmented hippocampus neuronal survival and promoted neurogenesis. Molecular studies revealed that PEG-CNPs promoted neurogenesis through the 5'-adenine monophosphate-activated protein kinase–protein kinase C–cyclic adenosine monophosphate response element-binding protein

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

    Science.gov (United States)

    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

  14. 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.

  15. 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.

  16. Intermittent hypoxia and neurorehabilitation.

    Science.gov (United States)

    Gonzalez-Rothi, Elisa J; Lee, Kun-Ze; Dale, Erica A; Reier, Paul J; Mitchell, Gordon S; Fuller, David D

    2015-12-15

    In recent years, it has become clear that brief, repeated presentations of hypoxia [i.e., acute intermittent hypoxia (AIH)] can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 yr. In 1980, Millhorn et al. (Millhorn DE, Eldridge FL, Waldrop TG. Respir Physiol 41: 87-103, 1980) showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 min (i.e., a "respiratory memory"). AIH elicits similar phrenic "long-term facilitation" (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003 to present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and noninvasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors. PMID:25997947

  17. The adverse pial arteriolar and axonal consequences of traumatic brain injury complicated by hypoxia and their therapeutic modulation with hypothermia in rat

    OpenAIRE

    Gao, Guoyi; Oda, Yasutaka; Wei, Enoch P.; Povlishock, John T.

    2009-01-01

    This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone, IAI and hypoxia, IAI and hypox...

  18. [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].

    Science.gov (United States)

    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

  19. 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.

  20. Imaging Tumor Hypoxia to Advance Radiation Oncology

    OpenAIRE

    Lee, Chen-Ting; Boss, Mary-Keara; Dewhirst, Mark W.

    2014-01-01

    Significance: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance. Recent Advances: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in p...

  1. Evaluation of the visual analog score (VAS to assess acute mountain sickness (AMS in a hypobaric chamber.

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    Jialin Wu

    Full Text Available The visual analog score (VAS is widely used in clinical medicine to evaluate the severity of subjective symptoms. There is substantial literature on the application of the VAS in medicine, especially in measuring pain, nausea, fatigue, and sleep quality. Hypobaric chambers are utilized to test and exercise the anaerobic endurance of athletes. To this end, we evaluated the degree of AMS using the visual analog scale (VAS in a hypobaric chamber in which the equivalent altitude was increased from 300 to 3500 m.We observed 32 healthy young men in the hypobaric chamber (Guizhou, China and increased the altitude from 300 to 3500 m. During the five hours of testing, we measured the resting blood oxygen saturation (SaO2 and heart rate (HR. Using the VAS, we recorded the subjects' ratings of their AMS symptom intensity that occurred throughout the phase of increasing altitude at 300 m, 1500 m, 2000 m, 2500 m, 3000 m, and 3500 m.During the phase of increasing altitude in the hypobaric chamber, the patients' SaO2 was 96.8 ± 0.8% at 300 m and 87.5 ± 4.1% at 3500 m (P<0.05 and their HR was 79.0 ± 8.0 beats/minute at 300 m and 79.3 ± 11.3 beats/minute at 3500 m. The incidence of symptoms significantly increased from 21.9% at an altitude of 1000 m to 65.6% at an altitude of 3500 m (P<0.05. The composite VAS score, which rated the occurrence of four symptoms (headache, dizziness, fatigue, and gastrointestinal discomfort, was significantly correlated with elevation (P<0.01.Based on the experimental data, the VAS can be used as an auxiliary diagnostic method of Lake Louise score to evaluate AMS and can show the changing severity of symptoms during the process of increased elevation in a hypobaric chamber; it also reflects a significant correlation with altitude.

  2. 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.

  3. 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.

  4. Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis

    OpenAIRE

    Beyer, C.; Schett, G; Gay, S; Distler, O.; Distler, J.H. W.

    2009-01-01

    Autoimmunity, microangiopathy and tissue fibrosis are hallmarks of systemic sclerosis (SSc). Vascular alterations and reduced capillary density decrease blood flow and impair tissue oxygenation in SSc. Oxygen supply is further reduced by accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Therefore, severe hypoxia is a characteristic feature of SSc and might contribute directly to the progression of the disease. Hypoxia stimulates the p...

  5. 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.

  6. 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

  7. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Conforti, L; Zhu, W H; Beitner-Johnson, D; Millhorn, D E

    1999-11-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatment of cells with pertussis toxin abolished D2-mediated inhibition of ICa. The D2-induced inhibition of ICa did not depend on protein kinase A (PKA), as it persisted both in the presence of a specific PKA inhibitor (PKI) and in PKA-deficient PC12 cells. Prolonged exposure to hypoxia (24 h) significantly reduced the level of Gi/o alpha immunoreactivity, but did not alter G beta levels. Furthermore, dialysis of recombinant G(o) alpha protein through the patch pipette restored the inhibitory effect of quinpirole in cells chronically exposed to hypoxia. We conclude that the attenuation of the D2-mediated inhibition of ICa by chronic hypoxia is caused by impaired receptor-G protein coupling, due to reduced levels of G(o) alpha protein. This attenuated feedback modulation of ICa by dopamine may allow for a more sustained Ca2+ influx and enhanced cellular excitation during prolonged hypoxia. PMID:10591061

  8. Clinical Biomarkers for Hypoxia Targeting

    OpenAIRE

    Le, Quynh-Thu; Courter, Don

    2008-01-01

    Tumor hypoxia or a reduction of the tissue oxygen tension is a key microenvironmental factor for tumor progression and treatment resistance in solid tumors. Because hypoxic tumor cells have been demonstrated to be more resistant to ionizing radiation, hypoxia has been a focus of laboratory and clinical research in radiation therapy for many decades. It is believed that proper detection of hypoxic regions would guide treatment options and ultimately improve tumor response. To date, most clinic...

  9. Hypoxia, Oxidative Stress and Fat

    Directory of Open Access Journals (Sweden)

    Nikolaus Netzer

    2015-06-01

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

  10. Hypoxia and Hypoxia-Inducible Factors in Leukemias.

    Science.gov (United States)

    Deynoux, Margaux; Sunter, Nicola; Hérault, Olivier; Mazurier, Frédéric

    2016-01-01

    Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic 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 hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, 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 leukemia is not considered a "solid" tumor, 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 leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias. PMID:26955619

  11. Hypoxia and hypoxia-inducible factors in leukaemias

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. The Gas Exchange, Ultrastructure and Stress Resistance of Lettuce Plants under Short-Term Hypobaric and Hypoxic Conditions%短期低压低氧下莴苣的气体交换、超微结构和抗逆特性

    Institute of Scientific and Technical Information of China (English)

    唐永康; 高峰; 郭双生

    2015-01-01

    To investigate the possibility of plants cultivation at hypobaria and hypoxia , the gas ex-change, ultrastructure and stress resistance of lettuce were conducted under short-term hypobaric and hy-poxic conditions.The gas exchange and growth of 25-day old lettuce (Lactuca sativa L.var.Rome) seed-lings were tested after 1-h or 24-h equilibration under two levels of total atmospheric pressure (101kPa and 30kPa)and three levels of oxygen partial pressure (21 kPa, 6 kPa and 2 kPa).The results showed that the biomass, ratio of root/shoot, water content and mineral contents of lettuce plants were not affect-ed by the changes of total atmospheric pressure and oxygen partial pressure;Under the same total pres-sure conditions (101 kPa or 30 kPa), hypoxia (6 kPa or 2 kPa) resulted in the increases of photosynthe-sis rate , soluble sugar and malondialdehyde and the reduction of dark respiration of lettuce leaves .The change of mitochondrion ultrastructure and the decrease of transpiration were found at 2 kPa oxygen par-tial pressure;Under the same oxygen partial pressure conditions , photosynthesis rate ,the chloroplast ul-trastructure ,the contents of chlorophyll and carotenoid of lettuce leaves were not affected by short-term hypobaric treatment (30 kPa) ,but the rates of dark respiration and transpiration increased and the con-tents of soluble sugar and malondialdehyde in lettuce leaves decreased .Lettuce can grow under short-term hypobaric and hypoxic conditions.Short-term hypoxia (6 kPa or 2 kPa) resulted in hypoxic stress and hypobaria(30 kPa) enhanced the stress resistance of lettuce .%为探索低压低氧环境中培养植物的可行性,研究了短期低压和低氧对莴苣气体交换、叶片超微结构和抗逆特性的影响。将莴苣植株(25天株龄)在两种总压(101 kPa和30 kPa )和三种氧分压(21 kPa、6 kPa和2 kPa)条件下进行了1小时和24小时平衡处理。发现短期低压和低氧均未影响莴苣植株生物量、根

  14. Hypoxia-mediated tumour targeting.

    Science.gov (United States)

    Binley, K; Askham, Z; Martin, L; Spearman, H; Day, D; Kingsman, S; Naylor, S

    2003-04-01

    Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad.CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy. PMID:12646859

  15. Lung Oxidative Damage by Hypoxia

    Directory of Open Access Journals (Sweden)

    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.

  16. Hypoxia induces TFE3 expression in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Sun, Zhi-Jun; Yu, Guang-Tao; Huang, Cong-Fa; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Zhang, Wen-Feng; Liu, Bing; Zhang, Lu

    2016-03-01

    To assess the role of transcription factor μE3 (TFE3) in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), human HNSCC tissue arrays were investigated for TFE3 expression. Human HNSCC tissues with neoadjuvant inductive chemotherapey (docetaxel, cisplatin and fluorouracil, TPF) and mice HNSCC tissues from transgenic mice model were evaluated for TFE3 expression and the hypoxia pathway. The roles of EGF/EGFR mediated hypoxia in TFE3 nuclear expression were analyzed in vitro and in vivo. TFE3 expression was higher in human HNSCC tissues compared with that in normal oral mucosa. Moreover, high TFE3 expression was related to HIF-1α, PAI-1, and EGFR, which demonstrated the activation of the hypoxia pathway in HNSCC tissues. Furthermore, elevated TFE3 expression was observed in HNSCC after cisplatin-based chemotherapy, and high TFE3 expression may indicate poor response to TPF inductive chemotherapy. Furthermore, similar changes with increased TFE3 were observed in HNSCC of the transgenic mouse HNSCC model. Hypoxic culture in the human HNSCC cell line increased TFE3 expression, which promoted cell survival under hypoxia. EGFR inhibiton by cetuximab could attenuate hypoxia-induced TFE3 in the HNSCC cell line and transgenic mouse HNSCC model. These findings indicated that TFE3 was an important hypoxia-induced transcriptional factor in HNSCC. TFE3 could be regarded as a durgable therapeutic oncotarget by EGFR inhibition. PMID:26872381

  17. [The intensity of respiration in pea and corn seedlings under high-altitude hypoxia].

    Science.gov (United States)

    Astafurova, T P; Ageev, B G; Sapozhnikova, V A; Ponomarev, Iu N; Zaĭtseva, T A; Zotnikova, A P

    1996-01-01

    Dynamics of CO2 gas-exchange and enzymatic activity of the respiratory metabolism of pea (Pisum sativum L.) and maize (Zea mays L.) seedlings during hypobaric hypoxia simulating the altitude of 5000 m above the sea level was studied. In the 48-hour chamber experiment (total barometric pressure is 54 kPa, partial O2 pressure is 11 kPa), the relative intensity of CO2 emission was found to increase and be essentially higher for pea than maize. Periodic reactions with small upward spikes and time offset were recorded in the pea plants. The initial increase of CO2 emission velocity by maize rapidly reached the level of saturation and since then remained constant. High velocity of the main catabolic ways and carboxylating activity in maize seedlings was the effect of hypoxic stress. Utilisation of respiratory substrates by pea seedlings was blocked at the Krebs cycle level, whereas glycolysis and oxidizing pentose phosphate pathways were activated. Weak activity of the carboxylate system does not provide refixation of endogenous carbon dioxide, excessive quantities of which invade the environment. PMID:8963291

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

    OpenAIRE

    Greijer, A.E.; Wall

    2004-01-01

    Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxi...

  19. 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

  20. Ghrelin Increases Lymphocytes in Chronic Normobaric Hypoxia

    OpenAIRE

    Mirzaie Bavil, Fariba; Mohaddes, Gisou; Ebrahimi, Hadi; Keyhanmanesh, Rana; Ghiyasi, Rafigheh; Alipour, Mohammad Reza

    2014-01-01

    Purpose: Hypoxia is a condition of decreased availability of oxygen. To adapt hypoxia, some changes in blood cells occur in the body. The aim of this study was to evaluate the effect of ghrelin on different types of blood cell in normobaric hypoxia situation.

  1. Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia

    Institute of Scientific and Technical Information of China (English)

    YANG Yuan-yuan; SHANG Jin; LIU Hui-guo

    2013-01-01

    Background Accumulated evidence shows that hypoxia can induce endothelial apoptosis,however the mechanism is still unknown.We hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress,leading to endothelial apoptosis.Methods Twenty-four 8-week male Sprague Dawley (SD) rats were divided into three groups:normoxia (NC) group,intermittent hypoxia (IH) group and persistent hypoxia (PH) group.TUNEL staining was performed to detect aortic arch endotheliar apoptosis,and immunohistochemistry for BIP,CHOP and caspase12 to test protein expression;human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured (with or without taurodeoxycholic acid (TUDCA) 10 mmol/L,100 mmol/L) and divided into four groups:NC group (20.8% O2 for 4 hours),PH1 group (5% O2 for 4 hours),PH2 group (5% O2 for 12 hours) and IH group (20.8% O2 and 5% O2 alternatively for 8 hours).Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each group.The expressions of GRP78,CHOP and caspase12 were detected by real-time quantitative reverse-transcription PCR.Result Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78,CHOP and caspase12 compared with the control,induction by intermittent hypoxia was slightly higher than persistent hypoxia.In the HUVEC experiment,TUDCA significantly reduced apoptosis and the expressions of GRP78,CHOP and caspase12.Conclusion Hypoxia,especially intermittent,can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway,which can be attenuated by taurodeoxycholic acid.

  2. 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

  3. Preconditioning with associated blocking of Ca2+ inflow alleviates hypoxia-induced damage to pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Zuheng Ma

    Full Text Available OBJECTIVE: Beta cells of pancreatic islets are susceptible to functional deficits and damage by hypoxia. Here we aimed to characterize such effects and to test for and pharmacological means to alleviate a negative impact of hypoxia. METHODS AND DESIGN: Rat and human pancreatic islets were subjected to 5.5 h of hypoxia after which functional and viability parameters were measured subsequent to the hypoxic period and/or following a 22 h re-oxygenation period. Preconditioning with diazoxide or other agents was usually done during a 22 h period prior to hypoxia. RESULTS: Insulin contents decreased by 23% after 5.5 h of hypoxia and by 61% after a re-oxygenation period. Preconditioning with diazoxide time-dependently alleviated these hypoxia effects in rat and human islets. Hypoxia reduced proinsulin biosynthesis ((3H-leucine incorporation into proinsulin by 35%. Preconditioning counteracted this decrease by 91%. Preconditioning reduced hypoxia-induced necrosis by 40%, attenuated lowering of proteins of mitochondrial complexes I-IV and enhanced stimulation of HIF-1-alpha and phosphorylated AMPK proteins. Preconditioning by diazoxide was abolished by co-exposure to tolbutamide or elevated potassium (i.e. conditions which increase Ca(2+ inflow. Preconditioning with nifedipine, a calcium channel blocker, partly reproduced effects of diazoxide. Both diazoxide and nifedipine moderately reduced basal glucose oxidation whereas glucose-induced oxygen consumption (tested with diazoxide was unaffected. Preconditioning with diaxoxide enhanced insulin contents in transplants of rat islets to non-diabetic rats and lowered hyperglycemia vs. non-preconditioned islets in streptozotocin-diabetic rats. Preconditioning of human islet transplants lowered hyperglycemia in streptozotocin-diabetic nude mice. CONCLUSIONS: 1 Prior blocking of Ca(2+ inflow associates with lesser hypoxia-induced damage, 2 preconditioning affects basal mitochondrial metabolism and accelerates

  4. 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...

  5. Preeclampsia, Hypoxia, Thrombosis, and Inflammation

    OpenAIRE

    Shamshirsaz, Amir A.; Michael Paidas; Graciela Krikun

    2011-01-01

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

  6. Evidence nitric oxide mediates the vasodepressor response to hypoxia in sino-denervated rats

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Miaokun; Reis, D.J. (Cornell Univ., New York, NY (United States))

    1992-01-01

    Systemic hypoxia, produced in deeply anesthetized, paralyzed rats in which arterial chemoreceptors were denervated, elicited a decrease in arterial pressure (AP) averaging {minus}47 mmHg. Systemic administration of N{sup G}-nitro-L-arginine (L-NO{sub 2}Arg), inhibitor of nitric oxide (NO) synthase, attenuated the hypoxic depressor response by 79% and elevated AP by 21 mmHg. The effects of L-NO{sub 2}Arg on the hypoxic depressor response and arterial pressure were reversed by systemic administration of L- but not D-arginine. Elevation of AP with arginine-vasopressin or reduction of AP with nitroprusside to the pre-L-NO{sub 2}Arg levels did not modify the fall of AP to hypoxia. Endogenous NO synthesized in vivo from L-arginine, mediates most of the hypoxia depressor response.

  7. 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

  8. Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Nicolas eBourdillon

    2015-10-01

    Full Text Available Background: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance.Methods: Twelve trained male cyclists [age: 31 ± 7 yr (mean ± SD] performed 15km time-trial cycling (TT and steady-state submaximal cycling (50, 100, and 150 W in normoxia and hypoxia (11% inspired O2 following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day. We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP during steady state cycling.Results: During steady state exercise, hypoxia elevated RV-RA gradient (p>0.05, while oral nitrate supplementation did not alter RV-RA gradient (p>0.05. During 15 km TT, hypoxia lowered muscle tissue oxygenation (p0.05. Conclusion: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.

  9. Enhancing lysosome biogenesis attenuates BNIP3-induced cardiomyocyte death

    OpenAIRE

    Ma, Xiucui; Godar, Rebecca J.; Liu, Haiyan; Diwan, Abhinav

    2012-01-01

    Hypoxia-inducible pro-death protein BNIP3 (BCL-2/adenovirus E1B 19-kDa interacting protein 3), provokes mitochondrial permeabilization causing cardiomyocyte death in ischemia-reperfusion injury. Inhibition of autophagy accelerates BNIP3-induced cell death, by preventing removal of damaged mitochondria. We tested the hypothesis that stimulating autophagy will attenuate BNIP3-induced cardiomyocyte death. Neonatal rat cardiac myocytes (NRCMs) were adenovirally transduced with BNIP3 (or LacZ as c...

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

    OpenAIRE

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

    2014-01-01

    Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The “gold standard” for detecting and characterizing of tumor hypoxia are the inv...

  11. HIF and pulmonary vascular responses to hypoxia

    OpenAIRE

    Shimoda, Larissa A.; Steven S Laurie

    2013-01-01

    In the lung, acute reductions in oxygen lead to hypoxic pulmonary vasoconstriction, whereas prolonged exposures to hypoxia result in sustained vasoconstriction, pulmonary vascular remodeling, and the development of pulmonary hypertension. Data from both human subjects and animal models implicate a role for hypoxia-inducible factors (HIFs), oxygen-sensitive transcription factors, in pulmonary vascular responses to both acute and chronic hypoxia. In this review, we discuss work from our laborat...

  12. 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.

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  14. 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.

  15. Hypobaric Treatment Effects on Chilling Injury, Mitochondrial Dysfunction, and the Ascorbate-Glutathione (AsA-GSH) Cycle in Postharvest Peach Fruit.

    Science.gov (United States)

    Song, Lili; Wang, Jinhua; Shafi, Mohammad; Liu, Yuan; Wang, Jie; Wu, Jiasheng; Wu, Aimin

    2016-06-01

    In this study, hypobaric treatment effects were investigated on chilling injury, mitochondrial dysfunction, and the ascorbate-glutathione (AsA-GSH) cycle in peach fruit stored at 0 °C. Internal browning of peaches was dramatically reduced by applying 10-20 kPa pressure. Hypobaric treatment markedly inhibited membrane fluidity increase, whereas it kept mitochondrial permeability transition pore (MPTP) concentration and cytochrome C oxidase (CCO) and succinic dehydrogenase (SDH) activity relatively high in mitochondria. Similarly, 10-20 kPa pressure treatment reduced the level of decrease observed in AsA and GSH concentrations, while it enhanced ascorbate peroxidase (APX), glutathione reductase (GR), and monodehydroascorbate reductase (MDHAR) activities related to the AsA-GSH cycle. Furthermore, comparative transcriptomic analysis showed that differentially expressed genes (DEGs) associated with the metabolism of glutathione, ascorbate, and aldarate were up-regulated in peaches treated with 10-20 kPa for 30 days at 0 °C. Genes encoding GR, MDHAR, and APX were identified and exhibited higher expression in fruits treated with low pressure than in fruits treated with normal atmospheric pressure. Our findings indicate that the alleviation of chilling injury by hypobaric treatment was associated with preventing mitochondrial dysfunction and triggering the AsA-GSH cycle by the transcriptional up-regulation of related enzymes. PMID:27195461

  16. Hypoxia, vascular smooth muscles and endothelium

    Directory of Open Access Journals (Sweden)

    Calvin K. Chan

    2013-02-01

    Full Text Available Hypoxia, or the lack of oxygen, has multiple impacts on the vascular system. The major molecular sensors for hypoxia at the cellular level are hypoxia inducible factor and heme oxygenase. Hypoxia also acts on the vasculature directly conveying its damaging effects through disruption of the control of vascular tone, particularly in the coronary circulation, enhancement of inflammatory responses and activation of coagulation pathways. These effects could be particularly detrimental under pathological conditions such as obstructive sleep apnea and other breathing disorders.

  17. 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.

  18. 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

  19. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

    OpenAIRE

    Kobayashi, Shuichi; Conforti, Laura; Zhu Dana Beitner-Johnson, Wylie H.; Millhorn, David E.

    1999-01-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatm...

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Beatrice Giuntoli

    2014-09-01

    Full Text Available 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

  2. The Influence of Exercise on Cognitive Performance in Normobaric Hypoxia.

    Science.gov (United States)

    Seo, Yongsuk; Burns, Keith; Fennell, Curtis; Kim, Jung-Hyun; Gunstad, John; Glickman, Ellen; McDaniel, John

    2015-12-01

    Although previous reports indicate that exercise improves cognitive function in normoxia, the influence of exercise on cognitive function in hypoxia is unknown. The purpose of this study was to determine if the impaired cognitive function in hypoxia can be restored by low to moderate intensity exercise. Sixteen young healthy men completed the ANAM versions of the Go/No-Go task (GNT) and Running Memory Continuous Performance Task (RMCPT) in normoxia to serve as baseline (B-Norm) (21% O2). Following 60 minutes of exposure to normobaric hypoxia (B-Hypo) (12.5% O2), these tests were repeated at rest and during cycling exercise at 40% and 60% of adjusted Vo2max. At B-Hypo, the % correct (p≤0.001) and throughput score (p≤0.001) in RMCPT were significantly impaired compared to B-Norm. During exercise at 40% (p=0.023) and 60% (p=0.006) of adjusted Vo2max, the throughput score in RMCPT improved compared to B-Hypo, and there was no significant difference in throughput score between the two exercise intensities. Mean reaction time also improved at both exercise intensities compared to B-Hypo (p≤0.028). Both peripheral oxygen saturation (Spo2) and regional cerebral oxygen saturation (rSo2) significantly decreased during B-Hypo (p≤0.001) and further decreased at 40% (p≤0.05) and 60% (p≤0.039) exercise. There was no significant difference in Spo2 or rSo2 between two exercise intensities. These data indicate that low to moderate exercise (i.e., 40%-60% adjusted Vo2max) may attenuate the risk of impaired cognitive function that occurs in hypoxic conditions. PMID:26214045

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

    DEFF Research Database (Denmark)

    Becker, Tracy A; Della Valle, Brian William; Gesser, Hans;

    2013-01-01

    by exogenous glucose. However, glucose did attenuate the fall in twitch force during severe hypoxia. Glucose uptake was assayed in non-contracting ventricle strips using 2-[(3)H] deoxy-d-glucose (2-DG) under aerobic and hypoxic conditions, at different incubation temperatures and with different inhibitors......-DG uptake or reduce lactate efflux in the presence of cytochalasin B. Increasing temperature (14 to 24°C) also did not increase 2-DG uptake, but decreasing temperature (14 to 4°C) reduced 2-DG uptake by 45%. In conclusion, exogenous glucose improves mechanical performance under hypoxia but not under...... any of the aerobic conditions applied. The extracellular concentration of glucose and cold temperature appear to determine and limit cardiomyocyte glucose uptake, respectively, and together may help define a metabolic strategy that relies predominantly on intracellular energy stores....

  4. Advances of Hypoxia and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xuebing LI

    2013-04-01

    Full Text Available Lung cancer is one of the malignant tumors with fastest growing rates in incidence and mortality in our country, also with largest threat to human health and life. However, the exact mechanisms underlying lung cancer development remain unclear. The microenvironment of tumor hypoxia was discovered in 1955, but hypoxia in lung cancer tissues had not been successfully detected till 2006. Further studies show that hypoxia not only functions through the resistance to radiotherapy, but also regulates lung cancer development, invasion, metastasis, chemotherapy resistance and prognosis through an important oncogene HIF (hypoxia inducible factor, with its regulators PHD (prolyl hydroxylase domain and pVHL (product of von Hippel-Lindau gene. Therefore, hypoxia, HIF, PHD and pVHL should be considered as potential therapeutic targets for lung cancer pathogenesis and progression.

  5. 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

  6. Hypoxia-targeted siRNA delivery.

    Science.gov (United States)

    Perche, F; Biswas, S; Wang, T; Zhu, L; Torchilin, V P

    2014-03-24

    Altered vasculature and the resultant chaotic tumor blood flow lead to the appearance in fast-growing tumors of regions with gradients of oxygen tension and acute hypoxia (less than 1.4% oxygen). Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy. Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy. This led to the development of hypoxia imaging agents, and the use of hypoxia-activated anticancer prodrugs. Here we show the first example of the hypoxia-induced siRNA uptake and silencing using a nanocarrier consisting of polyethyleneglycol 2000, azobenzene, polyethyleneimine (PEI)(1.8 kDa), and 1,2-dioleyl-sn-glycero-3-phosphoethanolamine (DOPE) units (the nanocarrier is referred to as PAPD), where azobenzene imparts hypoxia sensitivity and specificity. We report hypoxia-activated green fluorescent protein (GFP) silencing in vitro and its downregulation in GFP-expressing tumors after intravenous administration. The proposed nanoformulation represents a novel tumor-environment-responsive modality for cancer targeting and siRNA delivery. PMID:24554550

  7. A 26-Gene Hypoxia Signature Predicts Benefit from Hypoxia-Modifying Therapy in Laryngeal Cancer but Not Bladder Cancer

    NARCIS (Netherlands)

    Eustace, A.; Mani, N.; Span, P.N.; Irlam, J.J.; Taylor, J.; Betts, G.N.; Denley, H.; Miller, C.J.; Homer, J.J.; Rojas, A.M.; Hoskin, P.J.; Buffa, F.M.; Harris, A.L.; Kaanders, J.H.A.M.; West, C.M.

    2013-01-01

    PURPOSE: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefi

  8. Effects of 3, 4-Dihydroxyacetophenone on Cytosolic Calcium in Pulmonary Artery Endothelial and Smooth Muscle Cells during Acute Hypoxia

    Institute of Scientific and Technical Information of China (English)

    Farmanullah Wazir; WANG Dixun(王迪浔); HU Qinghua(胡清华)

    2004-01-01

    The effects of 3, 4-Dihydroxyacetophenone (3, 4-DHAP) on cytosolic free calcium[Ca2+ ]i in pulmonary artery endothelia (PAECs) and smooth muscle cells (PASMCs) during acute hypoxia were studied. Porcine pulmonary artery endothelial and smooth muscle cells (PASMCs)were cultured primarily, and they were divided into 4 groups: groups incubated under normoxia or hypoxia and those with or without treatment with 3, 4-DHAP. The [Ca2+ ]i of both PAECs and PASMCs was measured by determining the fluorescence of fura 2 AM on spetrofluorometer. Our results showed that hypoxia caused significant elevation of [Ca2+ ]i, in both PAECs and PASMCs,3, 4-DHAP could attenuate the hypoxic elevation of [Ca2+ ]i only in PASMCs but not in PAECs. It is concluded that 3, 4-DHAP decreases the hypoxic elevation of [Ca2+ ]i in PASMCs. This might contribute to its inhibitory effect on hypoxic pulmonary vasoconstriction.

  9. Regulation of Hypoxia-Induced Cell Death in Human Tenocytes

    OpenAIRE

    Min Liang; Cornell, Hannah R.; Nasim Zargar Baboldashti; Thompson, Mark S.; Carr, Andrew J.; Hulley, Philippa A

    2012-01-01

    Degenerate shoulder tendons display evidence of hypoxia. However tendons are relatively avascular and not considered to have high oxygen requirements and the vulnerability of tendon cells to hypoxia is unclear. Cultured human tenocytes were exposed to hypoxia and the cellular response detected using QPCR, Western blotting, viability, and ELISA assays. We find that tenocytes respond to hypoxia in vitro by activating classical HIF-1 α -driven pathways. Total hypoxia caused significant tenocyte ...

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

    DEFF Research Database (Denmark)

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

    1996-01-01

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

  11. Metabolic consequences of intermittent hypoxia.

    Science.gov (United States)

    O'Donnell, Christopher P

    2007-01-01

    Insulin resistance is being recognized increasingly as the basis for the constellation of metabolic abnormalities that make up the metabolic syndrome, or Syndrome X. Insulin resistance is also the primary risk factor for the development of type 2 diabetes mellitus, which is currently reaching epidemic proportions by affecting more than 170 million people worldwide. A combination of environmental and genetic factors have led to a dramatic rise in visceral adiposity, the predominant factor causing insulin resistance and type 2 diabetes. Visceral adiposity is also the major risk factor for the development of Sleep Apnea (SA)--an association that has fueled interest in the co-morbidity of SA and the metabolic syndrome, but hampered attempts to ascribe an independent causative role for Sleep Apnea in the development of insulin resistance and type 2 diabetes. Numerous population and clinic-based epidemiologic studies have shown associations, often independent of obesity, between SA (or surrogates such as snoring) and measures of glucose dysregulation or type 2 diabetes. However, treatment of SA with continuous positive airway pressure (CPAP) has not been conclusive in demonstrating improvements in insulin resistance, perhaps due to the overwhelming effects of obesity. Here we show that in lean, otherwise healthy mice that exposure to intermittent hypoxia produced whole-body insulin resistance as determined by the hyperinsulinemic euglycemic clamp and reduced glucose utilization in oxidative muscle fibers, but did not cause a change in hepatic glucose output. Furthermore, the increase in insulin resistance was not affected by blockade of the autonomic nervous system. We conclude that intermittent hypoxia can cause acute insulin resistance in otherwise lean healthy animals, and the response occurs independent of activation of the autonomic nervous system. PMID:18269187

  12. Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failure.

    Science.gov (United States)

    Marcus, Noah J; Pügge, Carolin; Mediratta, Jai; Schiller, Alicia M; Del Rio, Rodrigo; Zucker, Irving H; Schultz, Harold D

    2015-07-15

    In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 ± 2 ml/min) than in CHF-EXT animals (46 ± 2 ml/min, P hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF. PMID:26001414

  13. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  14. 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.

  15. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  16. 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...

  17. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  18. 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...

  19. 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...

  20. 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...

  1. Hypoxia and its implications in rheumatoid arthritis.

    Science.gov (United States)

    Quiñonez-Flores, Celia María; González-Chávez, Susana Aideé; Pacheco-Tena, César

    2016-01-01

    Alterations in tissue oxygen pressure contribute to a number of diseases, including rheumatoid arthritis (RA). Low partial pressure of oxygen, a condition known as hypoxia, is a relevant feature in RA since it is involved in angiogenesis, inflammation, apoptosis, cartilage degradation, energy metabolism, and oxidative damage. Therefore, alterations in hypoxia-related signaling pathways are considered potential mechanisms of disease pathogenesis. The objective of this review is to highlight and update our current knowledge of the role of hypoxia in the pathogenesis of RA. We describe the experimental evidence that RA synovial tissue exists in a hypoxic state, as well as the origin and involvement of synovial hypoxia in different aspects of the pathogenic process. PMID:27549205

  2. Editorial: an introduction and welcome to Hypoxia

    OpenAIRE

    Katschinski DM

    2013-01-01

    Dörthe M Katschinski Institute of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, GermanyHypoxia can influence many aspects of physiology and pathophysiology, including high altitude, embryonic development, wound healing, anemia, inflammation, cancer, and ischemic diseases, such as infarction and stroke. Researchers involved in hypoxia-related science are from a variety of different fields, and include cell biol...

  3. Editorial: an introduction and welcome to Hypoxia

    OpenAIRE

    Katschinski, Doerthe

    2013-01-01

    Dörthe M Katschinski Institute of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, GermanyHypoxia can influence many aspects of physiology and pathophysiology, including high altitude, embryonic development, wound healing, anemia, inflammation, cancer, and ischemic diseases, such as infarction and stroke. Researchers involved in hypoxia-related science are from a variety of different fields, and i...

  4. Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region.

    Science.gov (United States)

    Pastukh, Viktor M; Gorodnya, Olena M; Gillespie, Mark N; Ruchko, Mykhaylo V

    2016-07-01

    Mitochondria of mammalian cells contain multiple copies of mitochondrial (mt) DNA. Although mtDNA copy number can fluctuate dramatically depending on physiological and pathophysiologic conditions, the mechanisms regulating mitochondrial genome replication remain obscure. Hypoxia, like many other physiologic stimuli that promote growth, cell proliferation and mitochondrial biogenesis, uses reactive oxygen species as signaling molecules. Emerging evidence suggests that hypoxia-induced transcription of nuclear genes requires controlled DNA damage and repair in specific sequences in the promoter regions. Whether similar mechanisms are operative in mitochondria is unknown. Here we test the hypothesis that controlled oxidative DNA damage and repair in the D-loop region of the mitochondrial genome are required for mitochondrial DNA replication and transcription in hypoxia. We found that hypoxia had little impact on expression of mitochondrial proteins in pulmonary artery endothelial cells, but elevated mtDNA content. The increase in mtDNA copy number was accompanied by oxidative modifications in the D-loop region of the mitochondrial genome. To investigate the role of this sequence-specific oxidation of mitochondrial genome in mtDNA replication, we overexpressed mitochondria-targeted 8-oxoguanine glycosylase Ogg1 in rat pulmonary artery endothelial cells, enhancing the mtDNA repair capacity of transfected cells. Overexpression of Ogg1 resulted in suppression of hypoxia-induced mtDNA oxidation in the D-loop region and attenuation of hypoxia-induced mtDNA replication. Ogg1 overexpression also reduced binding of mitochondrial transcription factor A (TFAM) to both regulatory and coding regions of the mitochondrial genome without altering total abundance of TFAM in either control or hypoxic cells. These observations suggest that oxidative DNA modifications in the D-loop region during hypoxia are important for increased TFAM binding and ensuing replication of the mitochondrial

  5. 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.

  6. 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  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.

  7. 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.

  8. 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. PMID:25959851

  9. 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.

  10. Variable laser attenuator

    Science.gov (United States)

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Redmond H Paul

    2010-05-01

    Full Text Available 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.

  13. Chronic hypoxia reduces adenosine A2A receptor-mediated inhibition of calcium current in rat PC12 cells via downregulation of protein kinase A.

    Science.gov (United States)

    Kobayashi, S; Beitner-Johnson, D; Conforti, L; Millhorn, D E

    1998-10-15

    1. Adenosine has been shown to decrease Ca2+ current (ICa) and attenuate the hypoxia-induced enhancement of intracellular free Ca2+ ([Ca2+]i) in oxygen-sensitive rat phaeochromocytoma (PC12) cells. These effects are mediated via the adenosine A2A receptor and protein kinase A (PKA). The current study was undertaken to determine the effects of adenosine on Ca2+ current and hypoxia-induced change in [Ca2+]i during chronic hypoxia. 2. Whole cell patch-clamp studies revealed that the effect of adenosine on ICa was significantly reduced when PC12 cells were exposed to hypoxia (10 % O2) for 24 and 48 h. 3. Ca2+ imaging studies using fura-2 revealed that the anoxia-induced increase in [Ca2+]i was significantly enhanced when PC12 cells were exposed to 10 % O2 for up to 48 h. In contrast, the inhibitory effects of adenosine on anoxia-induced elevation of [Ca2+]i was significantly blunted in PC12 cells exposed to hypoxia for 48 h. 4. Northern blot analysis revealed that mRNA for the A2A receptor, which is the only adenosine receptor subtype expressed in PC12 cells, was significantly upregulated by hypoxia. Radioligand binding analysis with [3H]CGS21680, a selective A2A receptor ligand, showed that the number of adenosine A2A receptor binding sites was similarly increased during exposure to 10% O2 for 48 h. 5. PKA enzyme activity was significantly inhibited when PC12 cells were exposed to 10% O2 for 24 and 48 h. However, we found that hypoxia failed to induce change in adenosine- and forskolin-stimulated adenylate cyclase enzyme activity. Chronic hypoxia also did not alter the immunoreactivity level of the G protein Gsalpha, an effector of the A2 signalling pathway. 6. Whole cell patch-clamp analysis showed that the effect of 8-bromo-cAMP, an activator of PKA, on ICa was significantly attenuated during 48 h exposure to 10% O2.7. We conclude therefore that the reduced effect of adenosine on ICa and [Ca2+]i in PC12 cells exposed to chronic hypoxia is due to hypoxia

  14. 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.

  15. Functional genomics approach to hypoxia signaling.

    Science.gov (United States)

    Seta, Karen A; Millhorn, David E

    2004-02-01

    Mammalian cells require a constant supply of oxygen to maintain energy balance, and sustained hypoxia can result in cell death. It is therefore not surprising that sophisticated adaptive mechanisms have evolved that enhance cell survival during hypoxia. During the past few years, there have been a growing number of reports on hypoxia-induced transcription of specific genes. In this review, we describe a unique experimental approach that utilizes focused cDNA libraries coupled to microarray analyses to identify hypoxia-responsive signal transduction pathways and genes that confer the hypoxia-tolerant phenotype. We have used the subtractive suppression hybridization (SSH) method to create a cDNA library enriched in hypoxia-regulated genes in oxygen-sensing pheochromocytoma cells and have used this library to create microarrays that allow us to examine hundreds of genes at a time. This library contains over 300 genes and expressed sequence tags upregulated by hypoxia, including tyrosine hydroxylase, vascular endothelial growth factor, and junB. Hypoxic regulation of these and other genes in the library has been confirmed by microarray, Northern blot, and real-time PCR analyses. Coupling focused SSH libraries with microarray analyses allows one to specifically study genes relevant to a phenotype of interest while reducing much of the biological noise associated with these types of studies. When used in conjunction with high-throughput, dye-based assays for cell survival and apoptosis, this approach offers a rapid method for discovering validated therapeutic targets for the treatment of cardiovascular disease, stroke, and tumors. PMID:14715686

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

    OpenAIRE

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

    2013-01-01

    The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5), we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70%) decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQ...

  17. 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.

  18. Hypoxia in a neonate caused by intermittent positive pressure ventilation.

    OpenAIRE

    Beddis, I R; Silverman, M

    1980-01-01

    A newborn baby receiving mechanical ventilation was noted to have an extremely variable degree of hypoxia, despite the administration of 100% oxygen. The hypoxia was relieved rapidly when mechanical ventilation was withdrawn.

  19. Protein-bound Polysaccharide-K Inhibits Hedgehog Signaling Through Down-regulation of MAML3 and RBPJ Transcription Under Hypoxia, Suppressing the Malignant Phenotype in Pancreatic Cancer.

    Science.gov (United States)

    Yamasaki, Akio; Onishi, Hideya; Imaizumi, Akira; Kawamoto, Makoto; Fujimura, Akiko; Oyama, Yasuhiro; Katano, Mitsuo

    2016-08-01

    Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor. PMID:27466498

  20. 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.

  1. The Effect of Hypoxia on Mesenchymal Stem Cell Biology

    OpenAIRE

    Mostafa Ejtehadifar; Karim Shamsasenjan; Aliakbar Movassaghpour; Parvin Akbarzadehlaleh; Nima Dehdilani; Parvaneh Abbasi; Zahra Molaeipour; Mahshid Saleh

    2015-01-01

    Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, diff...

  2. Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving

    OpenAIRE

    Tian, Ran; Wang, Zhengfei; Niu, Xu; Zhou, Kaiya; Xu, Shixia; Yang, Guang

    2016-01-01

    Hypoxia was a major challenge faced by cetaceans during the course of secondary aquatic adaptation. Although physiological traits of hypoxia tolerance in cetaceans have been well characterized, the underlying molecular mechanisms remain unknown. We investigated the sequences of 17 hypoxia-tolerance-related genes in representative cetaceans to provide a comprehensive insight into the genetic basis of hypoxia tolerance in these animals. Genes involved in carrying and transporting oxygen in the ...

  3. Targeting tumour hypoxia to improve outcome of stereotactic radiotherapy

    DEFF Research Database (Denmark)

    Wittenborn, Thomas R; Horsman, Michael R

    2015-01-01

    BACKGROUND: Hypoxia is a characteristic feature of solid tumours that significantly reduces the efficacy of conventional radiation therapy. In this study we investigated the role of hypoxia in a stereotactic radiation schedule by using a variety of hypoxic modifiers in a preclinical tumour model...... OXi4503 and heat with the final 15 Gy had a significantly larger effect (TCD50 = 2 Gy). CONCLUSIONS: Clinically relevant modifiers of hypoxia effectively enhanced an equivalent stereotactic radiation treatment confirming the importance of hypoxia in such schedules....

  4. 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. PMID:27418545

  5. 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.

  6. 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.

  7. Cardiovascular Response to High Altitude Hypoxia

    Directory of Open Access Journals (Sweden)

    S. C. Manchanda

    1984-10-01

    Full Text Available Normal and abnormal cardiovascular response to high altitude (HA hypoxia were studied in 98 healthy subjects and in 15 patients with HA pulmonary oedema (HAPO and acute mountain sickness (AMS at an altitudeof 3,658 m. The healthy sea level (SL residents showed marked blood volume changes during the first week with pulmonary hypotension and depression of left ventricular (LV performance and physical work capacity (PWC. The HA natives, however, had better LV performance and PWC indicating a better adaptation to HA hypoxia. HAPO subjects showed evidence of severe pulmonary hypertension with normal left atrial pressures but the exact mechanism of this condition is still not clear. AMS subjects showed no circulatory abnormalities 'but had relative hypercapnia and severe hypoxemia suggesting that AMS may be causcd by relative hyposensitiveness of the respiratory centre to hypoxia or hypercapnia.

  8. 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...

  9. 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.

  10. 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

  11. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    Science.gov (United States)

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. PMID:25283246

  12. Diverse electron sources support denitrification under hypoxia in the obligate methanotroph Methylomicrobium album strain BG8

    Science.gov (United States)

    Kits, K. Dimitri; Campbell, Dustin J.; Rosana, Albert R.; Stein, Lisa Y.

    2015-01-01

    Aerobic methane-oxidizing bacteria (MOB) are a diverse group of microorganisms that are ubiquitous in natural environments. Along with anaerobic MOB and archaea, aerobic methanotrophs are critical for attenuating emission of methane to the atmosphere. Clearly, nitrogen availability in the form of ammonium and nitrite have strong effects on methanotrophic activity and their natural community structures. Previous findings show that nitrite amendment inhibits the activity of some cultivated methanotrophs; however, the physiological pathways that allow some strains to transform nitrite, expression of gene inventories, as well as the electron sources that support this activity remain largely uncharacterized. Here we show that Methylomicrobium album strain BG8 utilizes methane, methanol, formaldehyde, formate, ethane, ethanol, and ammonia to support denitrification activity under hypoxia only in the presence of nitrite. We also demonstrate that transcript abundance of putative denitrification genes, nirS and one of two norB genes, increased in response to nitrite. Furthermore, we found that transcript abundance of pxmA, encoding the alpha subunit of a putative copper-containing monooxygenase, increased in response to both nitrite and hypoxia. Our results suggest that expression of denitrification genes, found widely within genomes of aerobic methanotrophs, allow the coupling of substrate oxidation to the reduction of nitrogen oxide terminal electron acceptors under oxygen limitation. The present study expands current knowledge of the metabolic flexibility of methanotrophs by revealing that a diverse array of electron donors support nitrite reduction to nitrous oxide under hypoxia. PMID:26500622

  13. Diverse electron sources support denitrification under hypoxia in the obligate methanotroph Methylomicrobium album strain BG8

    Directory of Open Access Journals (Sweden)

    K. Dimitri eKits

    2015-10-01

    Full Text Available Aerobic methane-oxidizing bacteria are a diverse group of microorganisms that are ubiquitous in natural environments. Along with anaerobic methane-oxidizing bacteria and archaea, aerobic methanotrophs are critical for attenuating emission of methane to the atmosphere. Clearly, nitrogen availability in the form of ammonium and nitrite have strong effects on methanotrophic activity and their natural community structures. Previous findings show that nitrite amendment inhibits the activity of some cultivated methanotrophs; however, the physiological pathways that allow some strains to transform nitrite, expression of gene inventories, as well as the electron sources that support this activity remain largely uncharacterized. Here we show that M. album strain BG8 utilizes methane, methanol, formaldehyde, formate, ethane, ethanol and ammonia to support denitrification activity under hypoxia only in the presence of nitrite. We also demonstrate that transcript abundance of putative denitrification genes, nirS and one of two norB genes, increased in response to nitrite. Furthermore, we found that transcript abundance of pxmA, encoding the alpha subunit of a putative copper-containing monooxygenase, increased in response to both nitrite and hypoxia. Our results suggest that expression of denitrification genes, found widely within genomes of aerobic methanotrophs, allow the coupling of substrate oxidation to the reduction of nitrogen oxide terminal electron acceptors under oxygen limitation. The present study expands current knowledge of the metabolic flexibility of methanotrophs by revealing that a diverse array of electron donors support nitrite reduction to nitrous oxide under hypoxia.

  14. Protein synthesis during hypoxia in fetal lambs

    International Nuclear Information System (INIS)

    The goal of this study was to test the hypothesis that the rate of fetal protein synthesis decreases during fetal hypoxia. Catheters were inserted into 13 sheep fetuses under maternal spinal and local fetal anesthesia. Five days after surgery, an infusion of L-[14C]tyrosine was begun. Measurements were first made when tyrosine-specific activity reached steady state at 3 h and then again 3 h after fetal oxygen delivery was reduced by lowering the maternal inspired oxygen concentration. Umbilical blood flow was measured by injecting microspheres containing one of five radiolabels into the inferior venacava. Fetal tyrosine uptake across the umbilical circulation was 1.34 +/- 0.20 μ mol x kg-1 x min-1 during normoxia and decreased to 0.72 +/- 0.12 μ mol x kg-1 x min-1 during hypoxia. Tyrosine use from the plasma compartment was 1.25 +/- 0.18 μ mol x kg-1 x min-1 during normoxia and decreased to 0.64 +/- 0.12 μ mol x kg-1 x min-1 during hypoxia. Fetal tyrosine use decreased during reduced oxygen delivery because the rate of tyrosine use for fetal protein synthesis decreased. Fetal oxygen consumption decreased by 40 μ mol x kg-1 x min-1 during hypoxia. Decreased protein synthesis reduced the energy needed for protein synthesis and explained 28 μ mol x kg-1 x min-1 of this reduction

  15. 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

  16. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

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

    2014-01-01

    be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET...

  17. 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.

  18. 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

  19. Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism.

    Science.gov (United States)

    Beitner-Johnson, D; Millhorn, D E

    1998-07-31

    To investigate signaling mechanisms by which hypoxia regulates gene expression, we examined the effect of hypoxia on the cyclic AMP response element-binding protein (CREB) in PC12 cells. Exposure to physiological levels of hypoxia (5% O2, approximately 50 mm Hg) rapidly induced a persistent phosphorylation of CREB on Ser133, an event that is required for CREB-mediated transcriptional activation. Hypoxia-induced phosphorylation of CREB was more robust than that induced by any other stimulus tested, including forskolin, depolarization, and osmotic stress. Furthermore, this effect was not mediated by any of the previously known signaling pathways that lead to phosphorylation of CREB, including protein kinase A, calcium/calmodulin-dependent protein kinase, protein kinase C, ribosomal S6 kinase-2, and mitogen-activated protein kinase-activated protein kinase-2. Hypoxic activation of a CRE-containing reporter (derived from the 5'-flanking region of the tyrosine hydroxylase gene) was attenuated markedly by mutation of the CRE. Thus, a physiological reduction in O2 levels induces a functional phosphorylation of CREB at Ser133 via a novel signaling pathway. PMID:9677418

  20. Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis.

    Science.gov (United States)

    Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

    2016-01-01

    Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

  1. 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.

  2. 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.

  3. Protective effects of myricetin on acute hypoxia-induced exercise intolerance and mitochondrial impairments in rats.

    Directory of Open Access Journals (Sweden)

    Dan Zou

    Full Text Available Exercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro.Male rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM. The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA. mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence.Myricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up-regulating the expressions of mitochondrial biogenesis-related regulators, in addition, AMP-activated protein kinase(AMPK plays a crucial role in this process.Myricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis.

  4. Hypoxia-induced hypothermia mediated by GABA in the rostral parapyramidal area of the medulla oblongata.

    Science.gov (United States)

    Osaka, T

    2014-05-16

    Hypoxia evokes a regulated decrease in the body core temperature (Tc) in a variety of animals. The neuronal mechanisms of this response include, at least in part, glutamatergic activation in the lateral preoptic area (LPO) of the hypothalamus. As the sympathetic premotor neurons in the medulla oblongata constitute a cardinal relay station in the descending neuronal pathway from the hypothalamus for thermoregulation, their inhibition can also be critically involved in the mechanisms of the hypoxia-induced hypothermia. Here, I examined the hypothesis that hypoxia-induced hypothermia is mediated by glutamate-responsive neurons in the LPO that activate GABAergic transmission in the rostral raphe pallidus (rRPa) and neighboring parapyramidal region (PPy) of the medulla oblongata in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. Unilateral microinjection of GABA (15nmol) into the rRPa and PPy regions elicited a prompt increase in tail skin temperature (Ts) and decreases in Tc, oxygen consumption rate (VO2), and heart rate. Next, when the GABAA receptor blocker bicuculline methiodide (bicuculline methiodide (BMI), 10pmol) alone was microinjected into the rRPa, it elicited unexpected contradictory responses: simultaneous increases in Ts, VO2 and heart rate and a decrease in Tc. Then, when BMI was microinjected bilaterally into the PPy, no direct effect on Ts was seen; and thermogenic and tachycardic responses were slight. However, pretreatment of the PPy with BMI, but not vehicle saline, greatly attenuated the hypothermic responses evoked by hypoxic (10%O2-90%N2, 5min) ventilation or bilateral microinjections of glutamate (5nmol, each side) into the LPO. The results suggest that hypoxia-induced hypothermia was mediated, at least in part, by the activation of GABAA receptors in the PPy. PMID:24607346

  5. 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.

  6. Cross acclimation between heat and hypoxia: Heat acclimation improves cellular tolerance and exercise performance in acute normobaric hypoxia

    Directory of Open Access Journals (Sweden)

    Ben James Lee

    2016-03-01

    Full Text Available Background. The potential for cross acclimation between environmental stressors is not well understood. Thus the aim of this investigation was to determine the effect of fixed-workload heat or hypoxic acclimation on cellular, physiological and performance responses during post acclimation hypoxic exercise in humans. Method. Twenty-one males (age 22 ± 5 years; stature 1.76 ± 0.07m; mass 71.8 ± 7.9kg; V ̇O2 peak 51 ± 7mL.kg-1.min-1 completed a cycling hypoxic stress test (HST and self-paced 16.1km time trial (TT before (HST1, TT1, and after (HST2, TT2 a series of 10 daily 60 min training sessions (50% N V ̇O2peak in control (CON, n = 7; 18°C, 35%RH, hypoxic (HYP, n = 7; or hot (HOT, n = 7; 40°C, 25% RH conditions. Results. TT performance in hypoxia was improved following both acclimation treatments, HYP (-3:16 ± 3:10 mins:sec; p = 0.0006 and HOT (-2:02 ± 1:02 mins:sec; p = 0.005, but unchanged after CON (+0:31 ± 1:42 mins:sec. Resting monocyte heat shock protein 72 (mHSP72 increased prior to HST2 in HOT (62 ± 46% and HYP (58 ± 52%, but was unchanged after CON (9 ± 46%, leading to an attenuated mHSP72 response to hypoxic exercise in HOT and HYP HST2 compared to HST1 (p < 0.01. Changes in extracellular hypoxia-inducible factor 1-α followed a similar pattern to those of mHSP72. Physiological strain index (PSI was attenuated in HOT (HST1 = 4.12 ± 0.58, HST2 = 3.60 ± 0.42; p = 0.007 as a result of a reduced HR (HST1 = 140 ± 14 b.min-1; HST2 131 ± 9 b.min-1 p = 0.0006 and Trectal (HST1 = 37.55 ± 0.18°C; HST2 37.45 ± 0.14°C; p = 0.018 during exercise. Whereas PSI did not change in HYP (HST1 = 4.82 ± 0.64, HST2 4.83 ± 0.63. Conclusion. Heat acclimation improved cellular and systemic physiological tolerance to steady state exercise in moderate hypoxia. Additionally we show, for the first time, that heat acclimation improved cycling time trial performance to a magnitude similar to that achieved by hypoxic acclimation.

  7. 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.

  8. 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.

  9. Hypoxia induces adipogenic differentitation of myoblastic cell lines

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-09-03

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

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Jitesh D Kawedia

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

  12. 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.

  13. 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. PMID:26898739

  14. Pathophysiology and clinical effects of chronic hypoxia.

    Science.gov (United States)

    Pierson, D J

    2000-01-01

    Hypoxia exists when there is a reduced amount of oxygen in the tissues of the body. Hypoxemia refers to a reduction in PO2 below the normal range, regardless of whether gas exchange is impaired in the lung, CaO2 is adequate, or tissue hypoxia exists. There are several potential physiologic mechanisms for hypoxemia, but in patients with COPD the predominant one is V/Q mismatching, with or without alveolar hypoventilation, as indicated by PaCO2. Hypoxemia caused by V/Q mismatching as seen in COPD is relatively easy to correct, so that only comparatively small amounts of supplemental oxygen (less than 3 L/min for the majority of patients) are required for LTOT. Although hypoxemia normally stimulates ventilation and produces dyspnea, these phenomena and the other symptoms and signs of hypoxia are sufficiently variable in patients with COPD as to be of limited value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale--right ventricular hypertrophy with or without overt right ventricular failure--in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, to an extent that parallels the degree to which resting mean pulmonary artery pressure is elevated. Although the severity of airflow obstruction as measured by FEV1 is the best correlate with overall prognosis in patients with COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of LTOT in patients with COPD have demonstrated a dose-response relationship between daily hours of oxygen use and survival. There is reason to believe that continuous, 24-hours-per-day oxygen use in appropriately selected patients would produce a survival benefit even greater than that shown in the NOTT and MRC studies. PMID:10771781

  15. Cardiovascular Response to High Altitude Hypoxia

    OpenAIRE

    Manchanda, S C

    1984-01-01

    Normal and abnormal cardiovascular response to high altitude (HA) hypoxia were studied in 98 healthy subjects and in 15 patients with HA pulmonary oedema (HAPO) and acute mountain sickness (AMS) at an altitudeof 3,658 m. The healthy sea level (SL) residents showed marked blood volume changes during the first week with pulmonary hypotension and depression of left ventricular (LV) performance and physical work capacity (PWC). The HA natives, however, had better LV performance and PWC indicating...

  16. Relaxin Protects Astrocytes from Hypoxia In Vitro

    OpenAIRE

    Willcox, Jordan M.; Alastair J S Summerlee

    2014-01-01

    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 ex...

  17. NASA Gulf of Mexico Initiative Hypoxia Research

    Science.gov (United States)

    Armstrong, Curtis D.

    2012-01-01

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

  18. Humans In Hypoxia: A Conspiracy Of Maladaptation?!

    Science.gov (United States)

    Dempsey, Jerome A; Morgan, Barbara J

    2015-07-01

    We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost. PMID:26136544

  19. 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

  20. 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.

  1. 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.

  2. Regulation of gene expression by hypoxia.

    Science.gov (United States)

    Millhorn, D E; Czyzyk-Krzeska, M; Bayliss, D A; Lawson, E E

    1993-12-01

    The present study was undertaken to determine if gene expression for tyrosine hydroxylase (TH), the rate limiting enzyme in the biosynthesis of catecholamines, is regulated in the carotid body, sympathetic ganglia and adrenal medulla by hypoxia. We found that a reduction in oxygen tension from 21% to 10% caused a substantial increase (200% at 1 hour and 500% at 6 hours exposure) in the concentration of TH mRNA in carotid body type I cells but not in either the sympathetic ganglia or adrenal gland. In addition, we found that hypercapnia, another natural stimulus of carotid body activity, failed to enhance TH mRNA in type I cells. Removal of the sensory and sympathetic innervation of the carotid body failed to prevent the induction of TH mRNA by hypoxia in type I cells. Our results show that TH gene expression is regulated by hypoxia in the carotid body but not in other peripheral catecholamine synthesizing tissue and that the regulatory mechanism is intrinsic to type I cells. PMID:7909954

  3. 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.

  4. Hypoxia in the changing marine environment

    International Nuclear Information System (INIS)

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

  5. Hypoxia in the changing marine environment

    Science.gov (United States)

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

    2013-03-01

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

  6. The role of hypoxia in intestinal inflammation.

    Science.gov (United States)

    Shah, Yatrik M

    2016-12-01

    Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD. PMID:26812949

  7. Inner Retinal Oxygen Delivery and Metabolism Under Normoxia and Hypoxia in Rat

    OpenAIRE

    Wanek, Justin; Teng, Pang-yu; Blair, Norman P.; Shahidi, Mahnaz

    2013-01-01

    Measurements of inner retinal oxygen delivery and metabolism arereported in rat under systemic normoxia and hypoxia. Blood flow compensation for the reduced oxygen availability maintained inner retinal oxygen delivery and metabolism during moderate hypoxia, but not under severe hypoxia.

  8. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    Science.gov (United States)

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  9. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer

    DEFF Research Database (Denmark)

    Overgaard, Jens; Eriksen, Jesper Grau; Nordsmark, Marianne;

    2005-01-01

    BACKGROUND: The concentration of osteopontin (SPP1) in plasma is associated with tumour hypoxia. The DAHANCA 5 trial found that the hypoxia radiosensitiser nimorazole significantly improved the outcome of radiotherapy for patients with head and neck cancer compared with placebo. However, whether...... all patients benefit from such modification of hypoxia is unclear. We aimed to assess whether the concentration of plasma osteopontin could predict response to the hypoxia radiosensitiser. METHODS: Plasma concentrations of osteopontin were measured by use of ELISA from stored samples of 320 patients...... can be improved by use of nimorazole. High concentrations of osteopontin can predict clinically relevant hypoxia, and might identify patients who will benefit from modification of hypoxia during radiotherapy....

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were.......81, P = 0.01). The present human EPO responses to hypoxia were lower than those which have previously been reported in rodents and humans. In contrast with the earlier rodent studies, it was found that human EPO production could not be triggered by short-term increases in pH and haemoglobin oxygen...

  11. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

    OpenAIRE

    Zhou, Guofei; Dada, Laura A.; Wu, Minghua; Kelly, Aileen; Trejo, Humberto; Zhou, Qiyuan; Varga, John; Sznajder, Jacob I.

    2009-01-01

    Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of α-smooth muscle actin (α-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat, and mouse AEC, ...

  12. 减压贮藏对冷藏枇杷果实品质和木质化败坏的影响%Effects of hypobaric storage on quality and flesh leatheriness of cold-stored loquat fruit

    Institute of Scientific and Technical Information of China (English)

    郜海燕; 宋丽丽; 周拥军; 杨颖; 陈文烜; 陈杭君; 毛金林; 郑永华

    2008-01-01

    为阐明低温减压贮藏对枇杷果实品质和木质化败坏的影响,该研究应用40~50 kPa压力于(0±0.5)℃下贮藏果实49 d,并每隔7 d测定果实的营养品质、出汁率、硬度、褐变指数、呼吸速率、乙烯产生速率、过氧化物酶(POD)和苯丙氨酸解氨酶(PAL)等木质化相关酶活性及木质素含量的变化.结果表明,减压处理可明显抑制冷藏枇杷果实的呼吸强度、乙烯产生和果实褐变,并保持较高的果实可溶性固形物、可滴定酸度和维生素C含量,抑制贮藏21 d后果实硬度的增加,减轻出汁率的下降,降低POD和PAL酶活性的上升趋势,抑制木质素含量的增加.另外,减压贮藏减轻冷藏枇杷果实的木质化败坏,可能与抑制POD和PAL酶活性有关.低温减压贮藏可有效保持果实食用品质,延长贮藏期,是适合枇杷果实贮藏的有效方法.%The study was conducted to determine the effects of hypobaric storage on quality changes and flesh leatheriness of cold-stored ioquat fruit. Freshly harvested loquat fruit were stored for 49 days under 40~50 kPa hypobaric pressure condition at (0±0.5)°C. Nutritional quality, extractable juice rate, flesh firmness, browning index, respiration rate, ethylene production rate, lignin content and activities of phenylalanine ammonium-lyase (PAL) and peroxidase (POD) that related to flesh leatheriness were analyzed at 7-day intervals during storage. The results indicated that hypobaric storage significantly reduced the rates of respiration and ethylene production, inhibited browning index, and maintained high contents of total soluble solids(TSS), total titratable acidity (TA) and vitamin C (Vc). Moreover, hypobaric storage inhibited the increase of POD and PAL activities, reduced their peak values, delayed the increases of flesh firmness and lignin content after 21 days, inhibited the decrease of extractable juice rate, thereby maintaining good eating quality and extending the storage life

  13. Regional genome transcriptional response of adult mouse brain to hypoxia

    Directory of Open Access Journals (Sweden)

    Lu Aigang

    2011-10-01

    Full Text Available Abstract Background Since normal brain function depends upon continuous oxygen delivery and short periods of hypoxia can precondition the brain against subsequent ischemia, this study examined the effects of brief hypoxia on the whole genome transcriptional response in adult mouse brain. Result Pronounced changes of gene expression occurred after 3 hours of hypoxia (8% O2 and after 1 hour of re-oxygenation in all brain regions. The hypoxia-responsive genes were predominantly up-regulated in hindbrain and predominantly down-regulated in forebrain - possibly to support hindbrain survival functions at the expense of forebrain cognitive functions. The up-regulated genes had a significant role in cell survival and involved both shared and unshared signaling pathways among different brain regions. Up-regulation of transcriptional signaling including hypoxia inducible factor, insulin growth factor (IGF, the vitamin D3 receptor/retinoid X nuclear receptor, and glucocorticoid signaling was common to many brain regions. However, many of the hypoxia-regulated target genes were specific for one or a few brain regions. Cerebellum, for example, had 1241 transcripts regulated by hypoxia only in cerebellum but not in hippocampus; and, 642 (54% had at least one hepatic nuclear receptor 4A (HNF4A binding site and 381 had at least two HNF4A binding sites in their promoters. The data point to HNF4A as a major hypoxia-responsive transcription factor in cerebellum in addition to its known role in regulating erythropoietin transcription. The genes unique to hindbrain may play critical roles in survival during hypoxia. Conclusion Differences of forebrain and hindbrain hypoxia-responsive genes may relate to suppression of forebrain cognitive functions and activation of hindbrain survival functions, which may coordinately mediate the neuroprotection afforded by hypoxia preconditioning.

  14. Control algorithms for dynamic attenuators

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Scott S., E-mail: sshsieh@stanford.edu [Department of Radiology, Stanford University, Stanford, California 94305 and Department of Electrical Engineering, Stanford University, Stanford, California 94305 (United States); Pelc, Norbert J. [Department of Radiology, Stanford University, Stanford California 94305 and Department of Bioengineering, Stanford University, Stanford, California 94305 (United States)

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  15. 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.

  16. Regulation of N-methyl-D-aspartate receptor expression and N-methyl-D-aspartate-induced cellular response during chronic hypoxia in differentiated rat PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Millhorn, D E

    2000-01-01

    The purpose of the present study was to examine the effect of chronic hypoxia on N-methyl-D-aspartate-mediated cellular responses in differentiated PC12 cells. PC12 cells were differentiated by treatment with nerve growth factor. Patch-clamp analysis in differentiated PC12 cells showed that extracellularly applied N-methyl-D-aspartate induced an inward current that was abolished by the presence of the N-methyl-D-aspartate receptor antagonist MK-801. Results from Ca(2+) imaging experiments showed that N-methyl-D-aspartate induced an elevation in intracellular free Ca(2+) which was also abolished by MK-801. We also examined the effect of hypoxia on the N-methyl-D-aspartate-induced current in nerve growth factor-treated cells. We found that the N-methyl-D-aspartate-induced inward current and the N-methyl-D-aspartate-induced elevation in intracellular free Ca(2+) were markedly attenuated by chronic hypoxia. We next examined the possibility that the reduced N-methyl-D-aspartate responsiveness was due to down-regulation of N-methyl-D-aspartate receptor levels. Northern blot and immunoblot analyses showed that both messenger RNA and protein levels for N-methyl-D-aspartate receptor subunit 1 were markedly decreased during hypoxia. However, the messenger RNA for N-methyl-D-aspartate receptor subunit 2C was increased, whereas the protein level for subunit 2C did not change. Our results indicate that differentiated PC12 cells express functional N-methyl-D-aspartate receptors and that chronic exposure to hypoxia attenuates the N-methyl-D-aspartate-induced Ca(2+) accumulation in these cells via down-regulation of N-methyl-D-aspartate receptor subunit 1. This mechanism may play an important role in protecting PC12 cells against hypoxic stress. PMID:11113364

  17. The effect of altitude hypoxia on glucose homeostasis in men

    DEFF Research Database (Denmark)

    Larsen, J J; Hansen, J M; Olsen, Niels Vidiendal;

    1997-01-01

    1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia...

  18. 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...

  19. Hypoxia in head and neck cancer: how much, how important?

    NARCIS (Netherlands)

    Janssen, H.L.K.; Haustermans, K.; Balm, A.J.M.; Begg, A.C.

    2005-01-01

    BACKGROUND: Hypoxia develops in tumors because of a less ordered, often chaotic, and leaky vascular supply compared with that in normal tissues. In preclinical models, hypoxia has been shown to be associated with treatment resistance and increased malignant potential. In the clinic, several reports

  20. 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

    level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P pressure (PiO2) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange...

  1. 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...

  2. 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

  3. Hypoxia-targeting antitumor prodrugs and photosensitizers

    International Nuclear Information System (INIS)

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

  4. WSB1: from homeostasis to hypoxia.

    Science.gov (United States)

    Haque, Moinul; Kendal, Joseph Keith; MacIsaac, Ryan Matthew; Demetrick, Douglas James

    2016-01-01

    The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein. PMID:27542736

  5. 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.

  6. 2014 Gulf of Mexico Hypoxia Forecast

    Science.gov (United States)

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2014-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 4,761 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 14,000 square kilometers (95% credible interval, 8,000 to 20,000) – an “average year”. Our forecast hypoxic volume is 50 km3 (95% credible interval, 20 to 77).

  7. 2013 Gulf of Mexico Hypoxia Forecast

    Science.gov (United States)

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2013-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 7,316 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 18,900 square kilometers (95% credible interval, 13,400 to 24,200), the 7th largest reported and about the size of New Jersey. Our forecast hypoxic volume is 74.5 km3 (95% credible interval, 51.5 to 97.0), also the 7th largest on record.

  8. Hypoxia in the changing marine environment

    Digital Repository Service at National Institute of Oceanography (India)

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

    . It is suggested that changes in system sensitivity pose a great challenge to the ability of long-term forecasting and additional work on incorporation of more complex features coupled with climate scenarios is needed (Evans et al 2011). Das et al used a high... dead zones and consequences for marine ecosystems Science 321 926–9 Evans M A et al 2011 Forecasting hypoxia in the Chesapeake Bay and Gulf of Mexico: model accuracy, precision, and sensitivity to ecosystem change Environ. Res. Lett. 6 015001 Forrest D...

  9. TRAIL restores DCA/metformin-mediated cell death in hypoxia.

    Science.gov (United States)

    Hong, Sung-Eun; Kim, Chang Soon; An, Sungkwan; Kim, Hyun-Ah; Hwang, Sang-Gu; Song, Jie-Young; Lee, Jin Kyung; Hong, Jungil; Kim, Jong-Il; Noh, Woo Chul; Jin, Hyeon-Ok; Park, In-Chul

    2016-09-23

    Previous studies have shown that hypoxia can reverse DCA/metformin-induced cell death in breast cancer cells. Therefore, targeting hypoxia is necessary for therapies targeting cancer metabolism. In the present study, we found that TRAIL can overcome the effect of hypoxia on the cell death induced by treatment of DCA and metformin in breast cancer cells. Unexpectedly, DR5 is upregulated in the cells treated with DCA/metformin, and sustained under hypoxia. Blocking DR5 by siRNA inhibited DCA/metformin/TRAIL-induced cell death, indicating that DR5 upregulation plays an important role in sensitizing cancer cells to TRAIL-induced cell death. Furthermore, we found that activation of JNK and c-Jun is responsible for upregulation of DR5 induced by DCA/metformin. These findings support the potential application of combining TRAIL and metabolism-targeting drugs in the treatment of cancers under hypoxia. PMID:27569287

  10. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.

    Science.gov (United States)

    Noman, Muhammad Zaeem; Buart, Stéphanie; Romero, Pedro; Ketari, Sami; Janji, Bassam; Mari, Bernard; Mami-Chouaib, Fathia; Chouaib, Salem

    2012-09-15

    Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve. PMID:22962263

  11. Branchial O(2) chemoreceptors in Nile tilapia Oreochromis niloticus: Control of cardiorespiratory function in response to hypoxia.

    Science.gov (United States)

    Zeraik, Vivian M; Belão, Thiago C; Florindo, Luiz Henrique; Kalinin, Ana L; Rantin, F Tadeu

    2013-09-01

    This study examined the distribution and orientation of gill O(2) chemoreceptors in Oreochromis niloticus and their role in cardiorespiratory responses to graded hypoxia. Intact fish, and a group with the first gill arch excised (operated), were submitted to graded hypoxia and their cardiorespiratory responses (oxygen uptake - V˙O(2) , breathing frequency - fR, ventilatory stroke volume - VT, gill ventilation - V˙G, O(2) extraction from the ventilatory current - EO(2) , and heart rate - fH) were compared. Their responses to bolus injections of NaCN into the bloodstream (internal) or ventilatory water stream (external) were also determined. The V˙O(2) of operated fish was significantly lower at the deepest levels of hypoxia. Neither reflex bradycardia nor ventilatory responses were completely abolished by bilateral excision of the first gill arch. EO(2) of the operated group was consistently lower than the intact group. The responses to internal and external NaCN included transient decreases in fH and increases in fR and Vamp (ventilation amplitude). These cardiorespiratory responses were attenuated but not abolished in the operated group, indicating that chemoreceptors are not restricted to the first gill arch, and are sensitive to oxygen levels in both blood and water.

  12. News about VDAC1 in Hypoxia

    Science.gov (United States)

    Mazure, N. M.

    2016-01-01

    The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1. PMID:27625993

  13. Adenosine modulates hypoxia-induced responses in rat PC12 cells via the A2A receptor.

    Science.gov (United States)

    Kobayashi, S; Conforti, L; Pun, R Y; Millhorn, D E

    1998-04-01

    1. The present study was undertaken to determine the role of adenosine in mediating the cellular responses to hypoxia in rat phaeochromocytoma (PC12) cells, an oxygen-sensitive clonal cell line. 2. Reverse transcriptase polymerase chain reaction studies revealed that PC12 cells express adenosine deaminase (the first catalysing enzyme of adenosine degradation) and the A2A and A2B adenosine receptors, but not the A1 or A3 adenosine receptors. 3. Whole-cell current- and voltage-clamp experiments showed that adenosine attenuated the hypoxia-induced membrane depolarization. The hypoxia-induced suppression of the voltage-sensitive potassium current (IK(V)) was markedly reduced by adenosine. Furthermore, extracellularly applied adenosine increased the peak amplitudes of IK(V) in a concentration-dependent manner. This increase was blocked by pretreatment not only with a non-specific adenosine receptor antagonist, 8-phenyltheophylline (8-PT), but also with a selective A2A receptor antagonist, ZM241385. 4. Ca2+ imaging studies using fura-2 acetoxymethyl ester (fura-2 AM) revealed that the increase in intracellular free Ca2+ during hypoxic exposure was attenuated significantly by adenosine. Voltage-clamp studies showed that adenosine inhibited the voltage-dependent Ca2+ currents (ICa) in a concentration-dependent fashion. This inhibition was also abolished by both 8-PT and ZM241385. 5. The modulation of both IK(V) and ICa by adenosine was prevented by intracellular application of an inhibitor of protein kinase A (PKA), PKA inhibitor fragment (6-22) amide. In addition, the effect of adenosine on either IK(V) or ICa was absent in PKA-deficient PC12 cells. 6. These results indicate that the modulatory effects of adenosine on the hypoxia-induced membrane responses of PC12 cells are likely to be mediated via activation of the A2A receptor, and that the PKA pathway is required for these modulatory actions. We propose that this modulation serves to regulate membrane excitability in

  14. 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.

  15. EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

    Science.gov (United States)

    Lu, Ankang; Zuo, Caojian; He, Yuhu; Chen, Guilin; Piao, Lingjuan; Zhang, Jian; Xiao, Bing; Shen, Yujun; Tang, Juan; Kong, Deping; Alberti, Sara; Chen, Di; Zuo, Shenkai; Zhang, Qianqian; Yan, Shuai; Fei, Xiaochun; Yuan, Fei; Zhou, Bin; Duan, Shengzhong; Yu, Yu; Lazarus, Michael; Su, Yunchao; Breyer, Richard M.; Funk, Colin D.; Yu, Ying

    2015-01-01

    Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro–MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension. PMID:25664856

  16. 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.

  17. Snail1 Mediates Hypoxia-Induced Melanoma Progression

    Science.gov (United States)

    Liu, Shujing; Kumar, Suresh M.; Martin, James S.; Yang, Ruifeng; Xu, Xiaowei

    2011-01-01

    Tumor hypoxia is a known adverse prognostic factor, and the hypoxic dermal microenvironment participates in melanomagenesis. High levels of hypoxia inducible factor (HIF) expression in melanoma cells, particularly HIF-2α, is associated with poor prognosis. The mechanism underlying the effect of hypoxia on melanoma progression, however, is not fully understood. We report evidence that the effects of hypoxia on melanoma cells are mediated through activation of Snail1. Hypoxia increased melanoma cell migration and drug resistance, and these changes were accompanied by increased Snail1 and decreased E-cadherin expression. Snail1 expression was regulated by HIF-2α in melanoma. Snail1 overexpression led to more aggressive tumor phenotypes and features associated with stem-like melanoma cells in vitro and increased metastatic capacity in vivo. In addition, we found that knockdown of endogenous Snail1 reduced melanoma proliferation and migratory capacity. Snail1 knockdown also prevented melanoma metastasis in vivo. In summary, hypoxia up-regulates Snail1 expression and leads to increased metastatic capacity and drug resistance in melanoma cells. Our findings support that the effects of hypoxia on melanoma are mediated through Snail1 gene activation and suggest that Snail1 is a potential therapeutic target for the treatment of melanoma. PMID:21996677

  18. Ventilatory adaptation to hypoxia occurs in serotonin-depleted rats.

    Science.gov (United States)

    Olson, E B

    1987-08-01

    To test the hypothesis that serotonin mediated respiratory activity is involved in ventilatory adaptation to hypoxia, rats were treated with parachlorophenylalanine (PCPA), a potent, long-acting inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin. In normoxia, a single, intraperitoneal injection of 300 mg PCPA/kg body weight decreased the Paco2 from a control level at 39.1 +/- 0.6 Torr (mean +/- 95% confidence limits) to 34.0 +/- 0.6 Torr measured during a period from 1 to 48 h following PCPA treatment. This PCPA-produced hyperventilation corresponds to an increase of 3.7 +/- 0.5 in the VA (BTPS)/Vco2 (STPD) ratio. Hyperventilation during ventilatory adaptation to hypoxia (PIO2 approximately equal to 90 Torr) was superimposed in an additive fashion on the underlying hyperventilation due to PCPA pretreatment. Specifically, PCPA pretreatment caused an average 3.5 +/- 1.2 increase in the VA/VCO2 ratio determined in acute (1 h) hypoxia, chronic (24 h) hypoxia and acute return to normoxia following chronic hypoxia. Since ventilatory adaptation to hypoxia occurred in rats treated with PCPA, the prolonged, serotonin mediated respiratory activity described by Millhorn et al. (1980b) is probably not important in ventilatory acclimatization to - or deacclimatization from - hypoxia. PMID:2957766

  19. Regulation of CREB by moderate hypoxia in PC12 cells.

    Science.gov (United States)

    Beitner-Johnson, D; Rust, R T; Hsieh, T; Millhorn, D E

    2000-01-01

    The mechanisms by which excitable cells adapt and respond to changes in O2 levels remain largely unknown. We have investigated the effect of hypoxia on the cyclic AMP response element binding protein (CREB) transcription factor. PC12 cells were exposed to moderate levels of hypoxia (5% O2) for various times between 20 min and 6 hr. We found that hypoxia rapidly and persistently induced ser133 phosphorylation of CREB. This effect was more robust than that produced by exposing PC12 cells to either forskolin, KCl, or NGF. This effect was not due to activation of any of the previously known CREB kinases, including PKA, CaMK, PKC, p70s6k, or MAPKAP kinase-2. Thus, hypoxia may induce activation of a novel CREB kinase. To test whether phosphorylation of CREB was associated with an activation of CRE-dependent gene expression, cells were transfected with wild type and mutated regions of the 5'-flanking region of the tyrosine hydroxylase (TH) gene fused to a CAT reporter gene. Mutation of the CRE element in a TH reporter gene reduced, but did not abolish, the effects of hypoxia on TH gene expression. However, hypoxia did not induce transactivation of a GAL4-luciferase reporter by a GAL4-CREB fusion protein. Thus, the mechanism by which hypoxia regulates CREB is distinct, and more complex, than that induced by forskolin, depolarization, or nerve growth factor. PMID:10849656

  20. Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving.

    Science.gov (United States)

    Tian, Ran; Wang, Zhengfei; Niu, Xu; Zhou, Kaiya; Xu, Shixia; Yang, Guang

    2016-03-01

    Hypoxia was a major challenge faced by cetaceans during the course of secondary aquatic adaptation. Although physiological traits of hypoxia tolerance in cetaceans have been well characterized, the underlying molecular mechanisms remain unknown. We investigated the sequences of 17 hypoxia-tolerance-related genes in representative cetaceans to provide a comprehensive insight into the genetic basis of hypoxia tolerance in these animals. Genes involved in carrying and transporting oxygen in the blood and muscle (hemoglobin-α and β, myoglobin), and genes involved in the regulation of vasoconstriction (endothelin-1, -2, and -3; endothelin receptor type A and B; adrenergic receptor α-1D; and arginine vasopressin) appear to have undergone adaptive evolution, evidence for positive selection on their particular sites, and radical physiochemical property changes of selected condons. Interestingly, "long-diving" cetaceans had relatively higher ω (dN/dS) values than "short-diving" cetaceans for the hemoglobin β gene, indicating divergent selective pressure presented in cetacean lineages with different diving abilities. Additionally, parallel positive selection or amino acid changes (ADRA1D: P50A, A53G,AVPR1B: I/V270T) among animals exposed to different hypoxia habitats reflect functional convergence or similar genetic mechanisms of hypoxia tolerance. In summary, positive selection, divergent selective pressures, and parallel evolution at the molecular level provided some new insights into the genetic adaptation of hypoxia tolerance. PMID:26912402

  1. Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Bettina Schaible

    Full Text Available Pseudomonas aeruginosa (P. aeruginosa is an opportunistic pathogen commonly associated with lung and wound infections. Hypoxia is a frequent feature of the microenvironment of infected tissues which induces the expression of genes associated with innate immunity and inflammation in host cells primarily through the activation of the hypoxia-inducible factor (HIF and Nuclear factor kappaB (NF-κB pathways which are regulated by oxygen-dependent prolyl-hydroxylases. Hypoxia also affects virulence and antibiotic resistance in bacterial pathogens. However, less is known about the impact of hypoxia on host-pathogen interactions such as bacterial adhesion and infection. In the current study, we demonstrate that hypoxia decreases the internalization of P. aeruginosa into cultured epithelial cells resulting in decreased host cell death. This response can also be elicited by the hydroxylase inhibitor Dimethyloxallyl Glycine (DMOG. Reducing HIF-2α expression or Rho kinase activity diminished the effects of hypoxia on P. aeruginosa infection. Furthermore, in an in vivo pneumonia infection model, application of DMOG 48 h before infection with P. aeruginosa significantly reduced mortality. Thus, hypoxia reduces P. aeruginosa internalization into epithelial cells and pharmacologic manipulation of the host pathways involved may represent new therapeutic targets in the treatment of P. aeruginosa infection.

  2. Effect of vitamin E on cerebral cortical oxidative stress and brain-derived neurotrophic factor gene expression induced by hypoxia and exercise in rats.

    Science.gov (United States)

    Sakr, H F; Abbas, A M; El Samanoudy, A Z

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is involved in the proliferation of neurons, and its expression increases significantly with exercise. We aimed to investigate the effects of chronic exercise (swimming) and sustained hypoxia on cortical BDNF expression in both the presence and absence of vitamin E. Sixty four male Sprague-Dawley rats were divided into two equal groups; a normoxic group and a hypoxic group. Both groups were equally subdivided into four subgroups: sedentary, sedentary with vitamin E, chronic exercise either with or without vitamin E supplementation. Arterial PO(2), and the levels of cortical malondialdehyde (MDA), antioxidants (reduced glutathione GSH, superoxide dismutase (SOD), catalase (CAT) and vitamin E) and BDNF gene expression were investigated. Hypoxia significantly increased MDA production and BDNF gene expression and decreased the antioxidants compared to control rats. Chronic exercise in hypoxic and normoxic rats increased MDA level and BDNF gene expression and decreased the antioxidants. Providing vitamin E supplementation to the hypoxic and normoxic rats significantly reduced MDA and BDNF gene expression and increased antioxidants. We conclude that sustained hypoxia and chronic exercise increased BDNF gene expression and induced oxidative stress. Moreover, vitamin E attenuated the oxidative stress and decreased BDNF gene expression in sustained hypoxia and chronic exercise which confirms the oxidative stress-induced stimulation of BDNF gene expression. PMID:25903950

  3. Interactions of adenosine, prostaglandins and nitric oxide in hypoxia-induced vasodilatation: in vivo and in vitro studies

    Science.gov (United States)

    Ray, Clare J; Abbas, Mark R; Coney, Andrew M; Marshall, Janice M

    2002-01-01

    Adenosine, prostaglandins (PG) and nitric oxide (NO) have all been implicated in hypoxia-evoked vasodilatation. We investigated whether their actions are interdependent. In anaesthetised rats, the PG synthesis inhibitors diclofenac or indomethacin reduced muscle vasodilatation evoked by systemic hypoxia or adenosine, but not that evoked by iloprost, a stable analogue of prostacyclin (PGI2), or by an NO donor. After diclofenac, the A1 receptor agonist CCPA evoked no vasodilatation: we previously showed that A1, but not A2A, receptors mediate the hypoxia-induced muscle vasodilatation. Further, in freshly excised rat aorta, adenosine evoked a release of NO, detected with an NO-sensitive electrode, that was abolished by NO synthesis inhibition, or endothelium removal, and reduced by ≈50 % by the A1 antagonist DPCPX, the remainder being attenuated by the A2A antagonist ZM241385. Diclofenac reduced adenosine-evoked NO release by ≈50 % under control conditions, abolished that evoked in the presence of ZM241385, but did not affect that evoked in the presence of DPCPX. Adenosine-evoked NO release was also abolished by the adenyl cyclase inhibitor 2′,5′-dideoxyadenosine, while dose-dependent NO release was evoked by iloprost. Finally, stimulation of A1, but not A2A, receptors caused a release of PGI2 from rat aorta, assessed by radioimmunoassay of its stable metabolite, 6-keto PGF1α, that was abolished by diclofenac. These results suggest that during systemic hypoxia, adenosine acts on endothelial A1 receptors to increase PG synthesis, thereby generating cAMP, which increases the synthesis and release of NO and causes muscle vasodilatation. This pathway may be important in other situations involving these autocoids. PMID:12356892

  4. Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats.

    Science.gov (United States)

    Morgan, Barbara J; Adrian, Russell; Wang, Zun-Yi; Bates, Melissa L; Dopp, John M

    2016-05-15

    We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for V̇co2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the V̇e/V̇co2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation. PMID:26917692

  5. 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.

  6. Mitochondrial physiology and reactive oxygen species production are altered by hypoxia acclimation in killifish (Fundulus heteroclitus).

    Science.gov (United States)

    Du, Sherry N N; Mahalingam, Sajeni; Borowiec, Brittney G; Scott, Graham R

    2016-04-15

    Many fish encounter hypoxia in their native environment, but the role of mitochondrial physiology in hypoxia acclimation and hypoxia tolerance is poorly understood. We investigated the effects of hypoxia acclimation on mitochondrial respiration, O2kinetics, emission of reactive oxygen species (ROS), and antioxidant capacity in the estuarine killifish ( ITALIC! Fundulus heteroclitus). Killifish were acclimated to normoxia, constant hypoxia (5 kPa O2) or intermittent diel cycles of nocturnal hypoxia (12 h:12 h normoxia:hypoxia) for 28-33 days and mitochondria were isolated from liver. Neither pattern of hypoxia acclimation affected the respiratory capacities for oxidative phosphorylation or electron transport, leak respiration, coupling control or phosphorylation efficiency. Hypoxia acclimation also had no effect on mitochondrial O2kinetics, but ITALIC! P50(the O2tension at which hypoxia inhibits respiration by 50%) was lower in the leak state than during maximal respiration, and killifish mitochondria endured anoxia-reoxygenation without any impact on mitochondrial respiration. However, both patterns of hypoxia acclimation reduced the rate of ROS emission from mitochondria when compared at a common O2tension. Hypoxia acclimation also increased the levels of protein carbonyls and the activities of superoxide dismutase and catalase in liver tissue (the latter only occurred in constant hypoxia). Our results suggest that hypoxia acclimation is associated with changes in mitochondrial physiology that decrease ROS production and may help improve hypoxia tolerance. PMID:26896545

  7. Hypoxia-Specific Cytotoxins in Cancer Therapy.

    Science.gov (United States)

    Brown; Siim

    1996-01-01

    Hypoxic-specific cytotoxins are a new, and as yet clinically untested, mode of treatment of solid tumors. If they can be given at high enough concentrations and sufficiently often, they should prove extremely effective both in combination with standard radiotherapy and also with certain chemotherapeutic drugs. It is likely that their optimum use will turn hypoxic cells in solid tumors from a therapeutic disadvantage to an advantage. In this report, we review the rationale for the use of hypoxia- cytotoxins, including both the theoretical basis for combining them with fractionated radiation and the preclinical results that have been obtained to date combing these agents with fractionated radiation. We also discuss the three major classes of bioreductive drugs, including the quinones (mitomycin C, porfiromycin, and E09), notroaromatic compounds (including RB6145 and various deoxyribonucleic acid [DNA] targeted aromatics), and finally the n-oxides of which tirapazamine is the lead compound. We also briefly discuss new approaches to bioreductive drug development. The best ways to use these agents are also covered. These include using them in combination with radiation, in combination with chemotherapy, and in combination with agents that increase tumor hypoxia. Finally, the importance of the selection of patients for clinical trials is illustrated by showing how dramatically the number of patients for clinical trials is illustrated by showing how dramatically the number of patients in a clinical trial has to increase to obtain statistical significance for a procedure targeted towards hypoxic cells if some of the patients in the trials have well-oxygenated tumors. PMID:10717159

  8. Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

    OpenAIRE

    Carreras, Alba; Kayali, Foaz; Zhang, Jing; Hirotsu, Camila; Wang, Yang; Gozal, David

    2012-01-01

    Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IHL) have not been extensively examined, it would appear that IHL and high-frequency intermittent hypoxia (IHH) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IHH (cycles of 90 s 6.4% O2 and 90 s 21% O...

  9. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    International Nuclear Information System (INIS)

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the 124I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-β-d-arabinofuranosyl-5-iodouracil (124I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped 124I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of 124I-FIAU was also compared with that of an exogenous hypoxic cell marker, 18F-fluoromisonidazole (FMISO). Our results showed that 124I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of 124I-FIAU and 18F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between 124I-FIAU and 18F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. (orig.)

  10. The Effect of Prenatal Hypoxia on Brain Development: Short- and Long-Term Consequences Demonstrated in Rodent Models

    Science.gov (United States)

    Golan, Hava; Huleihel, Mahmoud

    2006-01-01

    Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent…

  11. 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...

  12. Hypoxia-Responsive Copolymer for siRNA Delivery.

    Science.gov (United States)

    Perche, Federico; Biswas, Swati; Patel, Niravkumar R; Torchilin, Vladimir P

    2016-01-01

    A wide variety of nanomedicine has been designed for cancer therapy. Herein, we describe the synthesis and evaluation of a hypoxia-responsive copolymer for siRNA delivery (Perche et al., Angew Chem Int Ed Engl 53:3362-3366, 2014). The synthesis is achieved using established coupling chemistry and accessible purification procedures. A polyelectrolyte-lipid conjugate (polyethyleneimine 1.8 kDa-dioleyl-phosphatidylinositol, PEI-PE) and polyethylene glycol 2000 (PEG) were assembled via the hypoxia-sensitive azobenzene (Azo) unit to obtain the PEG-Azo-PEI-DOPE copolymer. This copolymer can condense siRNA and shows hypoxia-induced cellular internalization and reporter gene downregulation in vitro and tumor accumulation in vivo after parenteral administration (Perche et al., Angew Chem Int Ed Engl 53:3362-3366, 2014). We also detail procedures to evaluate hypoxia-targeted polymers both in monolayer cultures, cancer cell spheroids and in tumor xenografts murine models. PMID:26530922

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. Exercise performed at hypoxia influences mood state and anxiety symptoms

    Directory of Open Access Journals (Sweden)

    Jorge Fernando Tavares de Souza

    2015-06-01

    Full Text Available During hypoxia conditions, psychological states can be worsened. However, little information is available regarding the effect of physical exercise performed in hypoxia conditions on mood state and anxiety symptoms. The aim of the present study was to elucidate the acute effect of moderate physical exercise performed at hypoxia on mood states and anxiety symptoms in healthy young subjects. Ten volunteers were subjected to the following conditions: a normoxic condition (NC and a hypoxic condition (HC. They performed 45 min of physical exercise. Their anxiety symptoms and mood states were evaluated at the initial time point as well as immediately following and 30 and 60 min after the exercise session. Our results showed a significant increase in post-exercise anxiety symptoms and a significant decrease in mood scores immediately after and 30 min after exercise performed in the HC. Moderate physical activity performed at hypoxia condition increased post-exercise anxiety and worsened mood state.

  20. 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...

  1. 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...

  2. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  3. 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.

  4. ROE Long Island Sound Hypoxia Data Web Service 2012

    Data.gov (United States)

    U.S. Environmental Protection Agency — Point data of collection sites overlayed on raster of hypoxia water data. The raster is broken out into 5 color-coded categories of oxygen level. This map is an...

  5. Distribution of hypoxia and pycnocline off the Changjiang Estuary, China

    Science.gov (United States)

    Zhu, Jianrong; Zhu, Zhuoyi; Lin, Jun; Wu, Hui; Zhang, Jing

    2016-02-01

    The distributions of hypoxia and the pycnocline off the Changjiang Estuary were investigated by making several field observations from June 2 to 11, from July 18 to 23, from August 20 to 30, from October 3 to 13, 2006, and from August 27 to September 3, 2009. The observations from July 18 to 23, 2006, mainly focused on analyzing the relationship between hypoxia and the extension of the river plume and vertical stratification. In July, the Changjiang diluted water (CDW) was influenced by the easterly typhoon winds, causing it to extend northward rather than northeastward. By using the maximum vertical density gradient as a stratification intensity index, we found that the area of low ( 2.0 kg/m4), which indicated that the summer pycnocline can effectively block vertical DO exchange and maintain hypoxia near the bottom. The observed hypoxic area was 500 km2, which was much smaller than the hypoxic areas observed in previous studies, and occurred because of the enhanced mixing that resulted from Typhoon Bill. During the observation period of August 20-30, 2006, the maximum density gradient was weaker due to distinct low river discharge. No hypoxia was observed in the eastern and southeastern sea off the Changjiang Estuary where hypoxia often occurs. However, hypoxia occurred over a large area of 15,400 km2 in the northern observation domain where hypoxia rarely occurs. During June 2-11 and October 3-13, 2006, the maximum density gradient was weaker, and the area with low DO was smaller than in July 2006. This finding resulted from relatively low river discharge and weaker solar heating. Consequently, no hypoxia occurred in the bottom layer. The area of low DO was similar to that of the maximum vertical density gradient. From August 27 to September 3, 2009, high river discharge and strong solar heating produced a larger and more intense pycnocline. The hypoxic area reached 3735 km2 and was very similar to the area of the pycnocline, which was greater than 3.0 kg/m4

  6. 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.

  7. ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA

    OpenAIRE

    Jain, Rakesh K.

    2014-01-01

    Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors’ blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiother...

  8. International hypoxia symposium XVIII: 26 February–02 March 2013

    OpenAIRE

    Pun, Matiram; Basnyat, Buddha

    2013-01-01

    The 18th International Hypoxia Symposia, Lake Louise, Alberta, Canada, February 26–March 02, 2013, covered molecular basis of hypoxic responses (e.g., hypoxia inducible factor, nitrite, nitrate, and hemoglobin) and integrative physiology (e.g., exercise physiology, cerebral blood flow responses, live-high train-low, and population genetics). Free communications and poster sessions covered scientific areas from controlled lab settings to field settings of high altitudes (Andes to Himalayas).

  9. Increased hemoglobin O2 affinity protects during acute hypoxia.

    Science.gov (United States)

    Yalcin, Ozlem; Cabrales, Pedro

    2012-08-01

    Acclimatization to hypoxia requires time to complete the adaptation mechanisms that influence oxygen (O(2)) transport and O(2) utilization. Although decreasing hemoglobin (Hb) O(2) affinity would favor the release of O(2) to the tissues, increasing Hb O(2) affinity would augment arterial O(2) saturation during hypoxia. This study was designed to test the hypothesis that pharmacologically increasing the Hb O(2) affinity will augment O(2) transport during severe hypoxia (10 and 5% inspired O(2)) compared with normal Hb O(2) affinity. RBC Hb O(2) affinity was increased by infusion of 20 mg/kg of 5-hydroxymethyl-2-furfural (5HMF). Control animals received only the vehicle. The effects of increasing Hb O(2) affinity were studied in the hamster window chamber model, in terms of systemic and microvascular hemodynamics and partial pressures of O(2) (Po(2)). Pimonidazole binding to hypoxic areas of mice heart and brain was also studied. 5HMF decreased the Po(2) at which the Hb is 50% saturated with O(2) by 12.6 mmHg. During 10 and 5% O(2) hypoxia, 5HMF increased arterial blood O(2) saturation by 35 and 48% from the vehicle group, respectively. During 5% O(2) hypoxia, blood pressure and heart rate were 58 and 30% higher for 5HMF compared with the vehicle. In addition, 5HMF preserved microvascular blood flow, whereas blood flow decreased to 40% of baseline in the vehicle group. Consequently, perivascular Po(2) was three times higher in the 5HMF group compared with the control group at 5% O(2) hypoxia. 5HMF also reduced heart and brain hypoxic areas in mice. Therefore, increased Hb O(2) affinity resulted in hemodynamics and oxygenation benefits during severe hypoxia. This acute acclimatization process may have implications in survival during severe environmental hypoxia when logistic constraints prevent chronic acclimatization. PMID:22636677

  10. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury

    Science.gov (United States)

    Chang, Yoon-Kyung; Choi, Hyunsu; Jeong, Jin Young; Na, Ki-Ryang; Lee, Kang Wook

    2016-01-01

    Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury. PMID:27391020

  11. Seismic attenuation in fractured media

    International Nuclear Information System (INIS)

    The prime objective of this paper is to quantitatively estimate seismic attenuation caused by fractures with different physical parameters. In seismic wave simulation, the fractured media are treated as the anisotropic media and fractures are represented by frequency-dependent elastic constants. Based on numerical experiments with three different parameters, namely viscosity, porosity and the Lamé parameters, this paper has the following observations. First, seismic attenuation is not affected by the viscosity within fractures, although it increases with the increase of porosity and decreases with the increase of the Lamé parameters within fractures. Among the latter two parameters, seismic attenuation is more sensitive to the Lamé parameters than to the porosity. Second, for the attenuation anisotropy, low frequencies have more anisotropic effect than high frequencies. For example, a 50 Hz wavefield has the strongest anisotropy effect if compared to 100 and 150 Hz wavefields. The attenuation anisotropy for low frequency (say 50 Hz) is more sensitive to the viscosity than the porosity and the Lamé parameters have the weakest effect among these three parameters. These observations suggest that low-frequency seismic attenuation, and especially the attenuation anisotropy in low frequency, would have great potential for fluid discrimination within fractured media. (paper)

  12. 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.

  13. 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

  14. 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. PMID:26212931

  15. 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.

  16. 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.

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

    International Nuclear Information System (INIS)

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

  18. NITRIC OXIDE INTERFERES WITH HYPOXIA SIGNALING DURING COLONIC INFLAMMATION

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    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.

  19. 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.

  20. Molecular Imaging of Tumor Hypoxia: Existing Problems and Their Potential Model-Based Solutions.

    Science.gov (United States)

    Shi, Kuangyu; Ziegler, Sibylle I; Vaupel, Peter

    2016-01-01

    Molecular imaging of tissue hypoxia generates contrast in hypoxic areas by applying hypoxia-specific tracers in organisms. In cancer tissue, the injected tracer needs to be transported over relatively long distances and accumulates slowly in hypoxic regions. Thus, the signal-to-background ratio of hypoxia imaging is very small and a non-specific accumulation may suppress the real hypoxia-specific signals. In addition, the heterogeneous tumor microenvironment makes the assessment of the tissue oxygenation status more challenging. In this study, the diffusion potential of oxygen and of a hypoxia tracer for 4 different hypoxia subtypes: ischemic acute hypoxia, hypoxemic acute hypoxia, diffusion-limited chronic hypoxia and anemic chronic hypoxia are theoretically assessed. In particular, a reaction-diffusion equation is introduced to quantitatively analyze the interstitial diffusion of the hypoxia tracer [(18)F]FMISO. Imaging analysis strategies are explored based on reaction-diffusion simulations. For hypoxia imaging of low signal-to-background ratio, pharmacokinetic modelling has advantages to extract underlying specific binding signals from non-specific background signals and to improve the assessment of tumor oxygenation. Different pharmacokinetic models are evaluated for the analysis of the hypoxia tracer [(18)F]FMISO and optimal analysis model were identified accordingly. The improvements by model-based methods for the estimation of tumor oxygenation are in agreement with experimental data. The computational modelling offers a tool to explore molecular imaging of hypoxia and pharmacokinetic modelling is encouraged to be employed in the corresponding data analysis. PMID:27526129

  1. 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.

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

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    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.

  3. 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.

  4. 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

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

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    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.

  6. Protective effects of Humanin on hypoxia-induced neuronal death

    Institute of Scientific and Technical Information of China (English)

    Yunqi Zhu; Yanli Li; Jingyi Liu; Xiaorong Yang; Ce Zhang

    2009-01-01

    BACKGROUND: Humanin is a 24-amino acid peptide isolated from the brain of an Alzheimer's disease patient. Several studies have indicated that Humanin can protect cells against cytotoxicity induced by various insults.OBJECTIVE: To investigate the protective role of Humanin on hypoxia-induced neuronal death, and to determine the most appropriate therapeutic concentration of Humanin.DESIGN, TIME AND SETTING: Neuropathophysiological, randomized, controlled experiment, conducted at the Department of Physiology and Neurobiology, Shanxi Medical University, between March 2007 and October 2007.MATERIALS: Newborn Wistar rats, 5,5',6,6' tetrachloro-1,1',3,3'-tetraethyl- benzimidazolylcarbocyanine iodide (JC-1, USA), calcein-acetoxymethylester (calcein-AM, USA), and Humanin (Shanghai, China) were used in this study. METHODS: Primary cortical neurons were cultured with dulbecco's modified eagle's medium containing 15% fetal bovine serum. Cultures were divided into three groups: control, hypoxia, and hypoxia + Humanin. Various concentrations of Humanin (1, 10, and 20 μmol/L) were added to the cultures 16 hours prior to hypoxia induction. For hypoxic conditions, cells were maintained at 37 ℃ within an incubator chamber filled with 95% N2 and 5% CO2 for 24 hours. Cells in the control group were cultured in normal oxygen. MAIN OUTCOME MEASURES: Cell viability was determined through the use of the vital dye calcein-AM, and the number of live cells was determined. Mitochondrial membrane potential (ΔΨm) was assessed using the fluorescent probe JC-1. Mitochondrial permeability transition pore (mPTP) opening was determined with calcein-AM in the presence of cobalt chloride.RESULTS: (1) Cell viability: Hypoxia for 24 hours induced death in a large number of neurons. Pretreatment with 10 μmol/L and 20 μmol/L Humanin, 16 hours prior to hypoxia, protected cells against hypoxia. However, 1 μmol/L Humanin provided little protection. (2) ΔΨm: ΔΨm was reduced after 24-hour hypoxia

  7. 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.

  8. 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

  9. Identification of vasodilator-stimulated phosphoprotein (VASP) as a HIF-regulated tissue permeability factor during hypoxia

    OpenAIRE

    Rosenberger, Peter; Khoury, Joseph; Kong, Tianqing; Weissmüller, Thomas; Robinson, Andreas M; Colgan, Sean P.

    2007-01-01

    Increased tissue permeability is commonly associated with hypoxia of many origins. Since hypoxia-inducible factor (HIF) represents a predominant hypoxia signaling mechanism, we compared hypoxia-elicited changes in tissue barrier function in mice conditionally lacking intestinal epithelial hypoxia-inducible factor-1α (hif1a). Somewhat surprisingly, these studies revealed that mutant hif1a mice were protected from hypoxia-induced increases in intestinal permeability in vivo. Guided by microarra...

  10. Raquianestesia unilateral com bupivacaína hipobárica Raquianestesia unilateral con bupivacaína hipobárica Unilateral spinal anesthesia with hypobaric bupivacaine

    Directory of Open Access Journals (Sweden)

    Luiz Eduardo Imbelloni

    2002-09-01

    raquianestesia unilateral son la estabilidad hemodinámica, la satisfacción del paciente y la ausencia de cefalea pós-punción.BACKGROUND AND OBJECTIVES: Restricted sympathetic block during spinal anesthesia may minimize hemodynamic changes. In theory, the use of non-isobaric local anesthetics may induce unilateral anesthesia and limit sympathetic blockade to one side of the body. The local anesthetic dose and the time patients need to remain in the lateral position for achieving unilateral spinal anesthesia are not known. This prospective study investigated the incidence of unilateral spinal anesthesia following injection through a 27G Quincke needle of 0.15% hypobaric bupivacaine, prepared with 1.5 ml standard isobaric bupivacaine plus fentanyl (25 µg, in patients in the lateral position with the limb to be operated upwards. METHODS: Spinal anesthesia with 0.15% bupivacaine + fentanyl (25 µg was induced through a 27G Quincke needle in 22 ASA I and II patients undergoing orthopedic surgery. Dural puncture was performed with the patient in the lateral position with the side to be operated upwards. After removal of 3 to 5 ml of CSF, 5 ml of the hypobaric bupivacaine-fentanyl mixture were injected at a speed of 1 ml.15 s-1. Sensory and motor block (pinprick/scale 0 to 3 were compared between operated and contralateral sides. RESULTS: Motor and sensory blocks in operated and contralateral sides were significantly different in all moments for both groups. Unilateral spinal anesthesia was obtained in 71% of the patients. No hemodynamic changes were observed in any patient. No patient developed post-dural puncture headache. CONCLUSIONS: Hypobaric 0.15% bupivacaine (7.5 mg associated to fentanyl provided a predominantly unilateral block after twenty minutes in the lateral position. Major advantages of unilateral spinal anesthesia were hemodynamic stability, patient satisfaction and the absence of post-dural puncture headache.

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

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    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. Intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Chen, Xiaofei; Zhao, Tong; Huang, Xin; Wu, Liying; Wu, Kuiwu; Fan, Ming; Zhu, Lingling

    2016-05-01

    Increasing studies have shown protective effects of intermittent hypoxia on brain injury and heart ischemia. However, the effect of intermittent hypoxia on blood glucose metabolism, especially in diabetic conditions, is rarely observed. The aim of this study was to investigate whether intermittent hypoxia influences blood glucose metabolism in type 1 diabetic rats. Streptozotocin-induced diabetic adult rats and age-matched control rats were treated with intermittent hypoxia (at an altitude of 3 km, 4 h per day for 3 weeks) or normoxia as control. Fasting blood glucose, body weight, plasma fructosamine, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), pancreas β-cell mass, and hepatic and soleus glycogen were measured. Compared with diabetic rats before treatment, the level of fasting blood glucose in diabetic rats after normoxic treatment was increased (19.88 ± 5.69 mmol/L vs. 14.79 ± 5.84 mmol/L, p  0.05). Meanwhile, fasting blood glucose in diabetic rats after hypoxic treatment was also lower than that in diabetic rats after normoxic treatment (13.14 ± 5.77 mmol/L vs. 19.88 ± 5.69 mmol/L, pintermittent hypoxia was significantly lower than that in diabetic rats receiving normoxia (1.28 ± 0.11 vs. 1.39 ± 0.11, p intermittent hypoxia showed effect on the increase of soleus glycogen but not hepatic glycogen. We conclude that intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats and its regulation on muscular glycogenesis may play a role in the underlying mechanism. PMID:26902078

  13. 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.

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

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    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

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

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    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

  16. 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.

  17. 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.

  18. 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

  19. 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...

  20. Effect of Organic Enrichment and Hypoxia on the Biodiversity of Benthic Communities in Narragansett Bay

    Science.gov (United States)

    Excessive input of nitrogen to coastal waters leads to eutrophication and hypoxia that reduce biodiversity and impair key ecosystem services provided by benthic communities; for example, fish and shellfish production, bioturbation, nutrient cycling, and water filtration. Hypoxia ...

  1. Effect of Hypoxia on Ca2+ Concentration in Broiler's Cardiac Muscle Cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The purpose of this research was to study the effect of hypoxia on the Ca2+ concentration in broiler's cardiac muscle cells (CMCs). The concentration of Ca2+ in the CMC was observed using a laser scanning confocal microscope (LSCM). The results showed that hypoxia could significantly increase intracellular Ca2+ (normal oxygen, 99.3 ± 13.1; hypoxia, 129.4±24.3, P<0.01) in CMCs. The Ca2+ antagonist (nifedipine, verapamil) could significantly restrain the Ca2+ influx across the cell membrane of CMC treated by hypoxia (CMC: hypoxia + verapamil, 100.9 ± 28.2; hypoxia + nifedipine, 107.6± 27.7;P < 0.01). The results showed hypoxia could increase intracellular Ca2+ concentration of CMC, and the Ca2+ antagonist could restrain the Ca2+ influx across the cell membrane of CMC treated by hypoxia.

  2. Estimation of Water Vapour Attenuation And Rain Attenuation

    Directory of Open Access Journals (Sweden)

    K.Kalyana Srinivas

    2015-04-01

    Full Text Available Attenuation due to and water vapour and rain can severely degrade the radio wave propagation at centimeter or millimeter wavelengths. It restricts the path length of radio communication systems and limits the use of higher frequencies for line-of-sight microwave links and satellite communications. The attenuation will pose a greater problem to communication as the frequency of occurrence of heavy rain increases.In a tropical region, like Malaysia, where excessive rainfall is a common phenomenon throughout the year, the knowledge of the rain attenuation at the frequency of operation is extremely required for the design of a reliable terrestrial and earth space communication link at a particular location.

  3. The attenuation and the attenuators: strategies and tactics

    Directory of Open Access Journals (Sweden)

    Antonio Briz

    2013-12-01

    Full Text Available This work is inscribed in a research project (ES.POR.ATENUAÇÃO that seeks to analyze and explain the attenuator activity in different regional varieties of Spanish and Portuguese, in order to perform, subsequently, different contrastive intralinguistic and interlinguistic studies. In this article, we explain some of the theoretical and methodological principles on which are based the qualitative and quantitative analysis. And especially, we will refer to the concept of attenuation (Briz 1995, 2002, 2003, 2005, 2007a, 2012.

  4. Multi-transmitting formula for attenuating waves

    Institute of Scientific and Technical Information of China (English)

    陈少林; 廖振鹏

    2003-01-01

    The MTF is extended to case of attenuating incident wave by introducing an attenuation coefficient. The reflection coefficients of this modified MTF and MTF areevaluated and compared when an attenuating wave impinges on the boundary, and the results demonstrate that MTF can be used to absorb slightly attenuating wavesand the modified MTF is more capable of absorbing heavily attenuating waves than MTF. The accuracy of modified MTF is also tested by numerical examples of fluid saturated porous media.

  5. 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.

  6. Intramucosal–arterial PCO 2 gap fails to reflect intestinal dysoxia in hypoxic hypoxia

    OpenAIRE

    Dubin, Arnaldo; Murias, Gastón; Estenssoro, Elisa; Canales, Héctor; Badie, Julio; Pozo, Mario; Sottile, Juan P; Barán, Marcelo; Pálizas, Fernando; Laporte, Mercedes

    2002-01-01

    Introduction An elevation in intramucosal–arterial PCO 2 gradient (ΔPCO 2) could be determined either by tissue hypoxia or by reduced blood flow. Our hypothesis was that in hypoxic hypoxia with preserved blood flow, ΔPCO 2 should not be altered. Methods In 17 anesthetized and mechanically ventilated sheep, oxygen delivery was reduced by decreasing flow (ischemic hypoxia, IH) or arterial oxygen saturation (hypoxic hypoxia, HH), or no intervention was made (sham). In the IH group (n = 6), blood...

  7. Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat

    OpenAIRE

    Darnall, R.A.; McWilliams, S.; Schneider, R. W.; Tobia, C. M.

    2010-01-01

    Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups wer...

  8. Chronic Hypoxia Promotes Pulmonary Artery Endothelial Cell Proliferation through H2O2-Induced 5-Lipoxygenase

    OpenAIRE

    Porter, Kristi M.; Bum-Yong Kang; Adesina, Sherry E.; Murphy, Tamara C.; C Michael Hart; Sutliff, Roy L.

    2014-01-01

    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 stimula...

  9. Hypoxia Induces Transforming Growth Factor-β1 Gene Expression in the Pulmonary Artery of Rats via Hypoxia-inducible Factor-1α

    Institute of Scientific and Technical Information of China (English)

    Yongliang JIANG; Aiguo DAI; Qifang LI; Ruicheng HU

    2007-01-01

    The present study was undertaken to investigate the dynamic expression of hypoxia inducible factor- 1 α (HIF-1 α) and transforming growth factor-β 1 (TGF-β 1) in hypoxia-induced pulmonary hypertension of rats. It was found that mean pulmonary arterial pressure (mPAP) increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. HIF-1α mRNA staining was less positive in the control, hypoxia for 3 d and hypoxia for 7 d, but began to enhance significantly after 14 d of hypoxia, then remained stable. Expression of HIF-1α protein in the control was less positive, but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats.TGF-β1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, but showed no obvious changes after 3 or 7 d of hypoxia. In pulmonary tunica adventitia and tunica media,TGF-β1 protein staining was less positive in control rats, but was markedly enhanced after 3 d of hypoxia,reaching its peak after 7 d of hypoxia, and then weakening after 14 and 21 d of hypoxia. Western blotting showed that HIF-1α protein levels increased significantly after 7 d of hypoxia and then remained at a high level. TGF-βi protein level was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia, and then decreasing after 14 and 21 d of hypoxia. Linear correlation analysis showed that HIF-1αmRNA, TGF-β1 mRNA, TGF-β1 protein were positively correlated with mPAP, vessel morphometry and right ventricular hypertrophy index. TGF-β1 protein (tunica adventitia) was negatively correlated with HIF-1α mRNA. Taken together, our results suggest that changes in HIF-1α and TGF-β1 expression after hypoxia play an important role in hypoxia-induced pulmonary hypertension of rats.

  10. 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

  11. Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104.

    Directory of Open Access Journals (Sweden)

    Juliana Benito

    Full Text Available Recent studies indicate that interactions between leukemia cells and the bone marrow (BM microenvironment promote leukemia cell survival and confer resistance to anti-leukemic drugs. There is evidence that BM microenvironment contains hypoxic areas that confer survival advantage to hematopoietic cells. In the present study we investigated whether hypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxic BM areas in immunodeficient mice engrafted with acute lymphoblastic leukemia (ALL cells. Consistent with this finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings suggest to employ hypoxia-activated prodrugs to eliminate leukemia cells within hypoxic niches. Using several xenograft models, we demonstrated that administration of the hypoxia-activated dinitrobenzamide mustard, PR-104 prolonged survival and decreased leukemia burden of immune-deficient mice injected with primary acute lymphoblastic leukemia cells. Together, these findings strongly suggest that targeting hypoxia in leukemic BM is feasible and may significantly improve leukemia therapy.

  12. 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.

  13. Calcium-dependent activation of Pyk2 by hypoxia.

    Science.gov (United States)

    Beitner-Johnson, Dana; Ferguson, Tsuneo; Rust, Randy T; Kobayashi, Shuichi; Millhorn, David E

    2002-02-01

    The Pyk2 tyrosine kinase can be activated by both calcium-dependent and calcium-independent mechanisms. Exposure to moderate hypoxia (5% O(2)) induced a rapid and persistent tyrosine phosphorylation of Pyk2 in pheochromocytoma (PC12) cells. Hypoxia and KCl-depolarization increased the phosphotyrosine content of Pyk2 by twofold and fourfold, respectively. Both of these effects were abolished in the absence of extracellular calcium. There was a modest activation of MAPK in parallel with the onset of Pyk2 phosphorylation. However, there was no detectable activation of either JNK or c-src, two other known downstream targets of Pyk2. Thus, exposure to hypoxia may selectively target specific subsets of Pyk2 signalling pathways. PMID:11781137

  14. 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.

  15. 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.

  16. 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.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia...

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

    OpenAIRE

    Erkan, Murat Mert; Kong, Bo; Cheng, Tao; Wu, Weiwei; Regel, Ivonne; Raulefs, Susanne; Friess, Helmut; Esposito, Irene; Kleeff, Joerg; Michalski, Christoph W.

    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...

  19. Metabolic and locomotor responses of juvenile paddlefish Polyodon spathula to hypoxia and temperature

    Science.gov (United States)

    Hypoxia is an increasing problem in the natural habitats that the paddlefish (Polyodon spathula) has historically inhabited, and a potential problem in managed culture conditions. However, the effects of hypoxia on paddlefish are not well understood. In order to understand the effects of hypoxia on ...

  20. GABARAPL1 is required for increased EGFR membrane expression during hypoxia

    NARCIS (Netherlands)

    Keulers, T.G.; Schaaf, M.B.; Peeters, H.J.; Savelkouls, K.G.; Vooijs, M.A.; Bussink, J.; Jutten, B.; Rouschop, K.M.

    2015-01-01

    BACKGROUND AND PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed, amplified or mutated in various human epithelial tumors and hypoxia is a common feature of solid tumors. Both EGFR and hypoxia are associated with therapy resistance and poor treatment outcome. To survive hypoxia,

  1. Sound attenuation in magnetorheological fluids

    Science.gov (United States)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  2. 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 biased...... at different points in the current-voltage characteristic. Both numerical calculations based on the Tien-Gordon theory and 70-GHz microwave experiments have confirmed the wide dynamic range (more than 15-dB attenuation for one stage) and the low insertion loss in the ''open'' state. The performance of a fully...... integrated submillimeter receiver circuit which comprises a flux-flow oscillator (FFO) as local oscillator, a superconducting variable attenuator, and a microwave SIS detector with tuned-out capacitance is also reported....

  3. 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

    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.

  4. Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

    Science.gov (United States)

    Basting, Tyler M; Burke, Peter G R; Kanbar, Roy; Viar, Kenneth E; Stornetta, Daniel S; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-14

    In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.

  5. The effects of exercise under hypoxia on cognitive function.

    Directory of Open Access Journals (Sweden)

    Soichi Ando

    Full Text Available Increasing evidence suggests that cognitive function improves during a single bout of moderate exercise. In contrast, exercise under hypoxia may compromise the availability of oxygen. Given that brain function and tissue integrity are dependent on a continuous and sufficient oxygen supply, exercise under hypoxia may impair cognitive function. However, it remains unclear how exercise under hypoxia affects cognitive function. The purpose of this study was to examine the effects of exercise under different levels of hypoxia on cognitive function. Twelve participants performed a cognitive task at rest and during exercise at various fractions of inspired oxygen (FIO2: 0.209, 0.18, and 0.15. Exercise intensity corresponded to 60% of peak oxygen uptake under normoxia. The participants performed a Go/No-Go task requiring executive control. Cognitive function was evaluated using the speed of response (reaction time and response accuracy. We monitored pulse oximetric saturation (SpO2 and cerebral oxygenation to assess oxygen availability. SpO2 and cerebral oxygenation progressively decreased during exercise as the FIO2 level decreased. Nevertheless, the reaction time in the Go-trial significantly decreased during moderate exercise. Hypoxia did not affect reaction time. Neither exercise nor difference in FIO2 level affected response accuracy. An additional experiment indicated that cognitive function was not altered without exercise. These results suggest that the improvement in cognitive function is attributable to exercise, and that hypoxia has no effects on cognitive function at least under the present experimental condition. Exercise-cognition interaction should be further investigated under various environmental and exercise conditions.

  6. 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.

  7. 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. PMID:26023228

  8. Aging, Tolerance to High Altitude, and Cardiorespiratory Response to Hypoxia.

    Science.gov (United States)

    Richalet, Jean-Paul; Lhuissier, François J

    2015-06-01

    Richalet, Jean-Paul, and François J. Lhuissier. Aging, tolerance to high altitude, and cardiorespiratory response to hypoxia. High Alt Med Biol. 16:117-124, 2015.--It is generally accepted that aging is rather protective, at least at moderate altitude. Some anecdotal reports even mention successful ascent of peaks over 8000 m and even Everest by elderly people. However, very few studies have explored the influence of aging on tolerance to high altitude and prevalence of acute high altitude related diseases, taking into account all confounding factors such as speed of ascent, altitude reached, sex, training status, and chemo-responsiveness. Changes in physiological responses to hypoxia with aging were assessed through a cross-sectional 20-year study including 4675 subjects (2789 men, 1886 women; 14-85 yrs old) and a longitudinal study including 30 subjects explored at a mean 10.4-year interval. In men, ventilatory response to hypoxia increased, while desaturation was less pronounced with aging. Cardiac response to hypoxia was blunted with aging in both genders. Similar results were found in the longitudinal study, with a decrease in cardiac and an increase in ventilatory response to hypoxia with aging. These adaptive responses were less pronounced or absent in post-menopausal untrained women. In conclusion, in normal healthy and active subjects, aging has no deleterious effect on cardiac and ventilatory responses to hypoxia, at least up to the eighth decade. Aging is not a contraindication for high altitude, as far as no pathological condition interferes and physical fitness is compatible with the intensity of the expected physical demand of one's individual. Physiological evaluation through hypoxic exercise testing before going to high altitude is helpful to detect risk factors of severe high altitude-related diseases. PMID:25946570

  9. 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

  10. [EFFECT OF HYPOXIA ON THE CHARACTERISTICS OF HUMAN AUDITORY PERCEPTION].

    Science.gov (United States)

    Ogorodnikova, E A; Stolvaroya, E I; Pak, S P; Bogomolova, G M; Korolev, Yu N; Golubev, V N; Lesova, E M

    2015-12-01

    The effect of normobaric hypoxic hypoxia (single and interval training) on the characteristics of human hearing was investigated. The hearing thresholds (tonal audiograms), reaction time of subjects in psychophysical experiments (pause detection, perception of rhythm and target words), and short-term auditory memory were measured before and after hypoxia. The obtained data revealed improvement of the auditory sensitivity and characteristics of working memory, and increasing of response speed. It was demonstrated that interval hypoxic training had positive effect on the processes of auditory perception. PMID:26987233

  11. Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia.

    Science.gov (United States)

    Kim, Hyungsoo; Scimia, Maria C; Wilkinson, Deepti; Trelles, Ramon D; Wood, Malcolm R; Bowtell, David; Dillin, Andrew; Mercola, Mark; Ronai, Ze'ev A

    2011-11-18

    Defining the mechanisms underlying the control of mitochondrial fusion and fission is critical to understanding cellular adaptation to diverse physiological conditions. Here we demonstrate that hypoxia induces fission of mitochondrial membranes, dependent on availability of the mitochondrial scaffolding protein AKAP121. AKAP121 controls mitochondria dynamics through PKA-dependent inhibitory phosphorylation of Drp1 and PKA-independent inhibition of Drp1-Fis1 interaction. Reduced availability of AKAP121 by the ubiquitin ligase Siah2 relieves Drp1 inhibition by PKA and increases its interaction with Fis1, resulting in mitochondrial fission. High AKAP121 levels, seen in cells lacking Siah2, attenuate fission and reduce apoptosis of cardiomyocytes under simulated ischemia. Infarct size and degree of cell death were reduced in Siah2(-/-) mice subjected to myocardial infarction. Inhibition of Siah2 or Drp1 in hatching C. elegans reduces their life span. Through modulating Fis1/Drp1 complex availability, our studies identify Siah2 as a key regulator of hypoxia-induced mitochondrial fission and its physiological significance in ischemic injury and nematode life span. PMID:22099302

  12. 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.

  13. Hypoxia Inducible Factor-1 Alpha Correlates the Expression ofHeme Oxygenase 1 Gene in Pulmonary Arteries of Ratwith Hypoxia-induced Pulmonary Hypertension

    Institute of Scientific and Technical Information of China (English)

    Qi-FangLI; Ai-GuoDAI

    2004-01-01

    AbstractTo test the hypothesis that hypoxia inducible factor-1 alpha (HIF-1α)up-regulated theexpression of heme oxygenase-1 (HO-1) gene in pulmonary arteries of rats with hypoxia-induced pulmonaryhypertension, 8 male Wistar rats in each of 5 groups were exposed to hypoxia for 0, 3, 7, 14 or 21 d, respectively.Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index weremeasured. Lungs were inflation fixed for immunohistochemistry, in situ hybridization; frozen for latermeasurement of HO-1 enzyme activity, mPAP increased significantly after 7 d of hypoxia [(18.4 ± 0.4)mmHg, P<0.05], reaching its peak after 14 d of hypoxia, then remained stable. Pulmonary artery remodeling became to develop significantly after 14 d of hypoxia. HIF-1αprotein in control was poorly positive (0.05 ±0.01), but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterialtunica media, the levels of HIF-la protein were markedly up-regulated after 3 d and 7 d of hypoxia(0.20±0.02; 0.22 ± 0.02, P<0.05), then declined after 14 d and 21 d of hypoxia. HIF-mRNA stainingwas poorly positive in control, hypoxia for 3 and 7 d, but enhanced significantly after 14 d of hypoxia(0.20±0.02, P<0.05), then remained stable. HO-1 protein increased after 7 d of hypoxia (0.10±0.01,P<0.05), reaching its peak after 14 d of hypoxia (0.21 0.02, P<0.05), then remained stable. HO-1 mRNA increased after 3 d of hypoxia, reaching its peak after 7 d of hypoxia (0.17 ± 0.01, P<0.05), then declined.Linear correlation analysis showed that HIF-lα mRNA, HO-1 protein and mPAP were associatedwith pulmonary remodeling. HIF-1 α protein (tunica intima) was conversely correlated with HIF-1α mRNA(r=0.921, P<0.01), HO-1 protein was conversely correlated with HIF-1α protein (tunica intima)(r=0.821, P<0.01 ). HIF-1αand HO-1 were both involved in the pathogenesis of hypoxia-induced pulmonaryhypertension in rat. Hypoxia inducible factor-1 alpha

  14. 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.

  15. 不同减压处理对圣女果贮藏品质的影响%Effects of Different Hypobaric Treatment on Storage Quality of Cherry Tomatoes

    Institute of Scientific and Technical Information of China (English)

    庞凌云; 詹丽娟; 李瑜; 祝美云; 陈耀华

    2012-01-01

    将圣女果分别放在101.3 kPa(常压)、80、50、20 kPa下,每4 d测定相关指标,研究减压处理对圣女果贮藏品质的影响。结果表明:减压处理可降低采后圣女果的失重率、呼吸强度,抑制Vc含量、可滴定酸含量、可溶性固形物含量、原果胶含量的降低,减缓细胞质膜透性、花青苷含量的上升,从而保持了其贮藏期的品质,延缓其衰老速率,其中以50 kPa处理效果佳。%Cherry tomatoes were stored under different levels of pressure (101.3 kPa, 80 kPa, 50 kPa, 20 kPa). A series of parameters of cherry tomatoes were measured at intervals of4d to evaluate the preservation effect by hypobaric treatment. Results showed that hypobaric treatment could reduce the weight loss rate, respiratory intensity of cherry tomatoes, maintain Vc content, titration acidity, soluble solid content and protopectin content, restrain the rising of cytoplasm membrane permeability and anthocyanin content in some extent, and hold the better storage quali- ty. Cherry tomatoes treated with 50 kPa preserved the best quality during storage.

  16. Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat.

    Science.gov (United States)

    Darnall, R A; McWilliams, S; Schneider, R W; Tobia, C M

    2010-12-01

    Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures. PMID:20930126

  17. 适宜压力条件保持减压贮藏杏鲍菇品质%Optimum pressurecondition maintain quality ofPleurotus eryngii in hypobaric storage

    Institute of Scientific and Technical Information of China (English)

    李志刚; 宋婷; 郝利平; 常明昌; 石建春; 冯翠萍

    2015-01-01

    In order to study the effects of different hypobaric conditions (0.10, 0.06, 0.04, 0.02 MPa) on storage quality and physiological and biochemical indices of Pleurotus eryngii, the experiment was carried out withPleurotus eryngii as materials, which were vacuum-packed with 0.07 mm low density polyethylene bags, and stored in 4℃. The results showed that, compared with normal pressure (0.10 MPa), hypobaric storage under 0.06 and 0.04 MPa not only reduced the respiration rate ofPleurotus eryngii at different degrees and maintained the activities of superoxide dismutase (SOD) and catalase (CAT), but also inhibited the increase of malondialdehyde (MDA), which delayed aging process, and inhibited the activity of polyphenol oxidase (PPO), which delayed browning degree. So the hardness, springiness, cohesiveness, chewiness and the color of Pleurotus eryngii were better maintained under 0.06 and 0.04 MPa, among which the effect of hypobaric storage under 0.04 MPa was better. It also showed that, from 0.10 to 0.04 MPa, the lower the pressure, the better the effect of the hypobaric storage. But when Pleurotus eryngii was stored under 0.02 MPa, the changes of storage quality did not obey the law. Under this storage pressure, the change law of the respiration rate, the activity of CAT, the hardness of pileus, the springiness and chewiness of pileus and stipe all showed abnormal conditions. At the same time, abnormal conditions were found in the variations of the activity of PPO, the color and the MDA content ofPleurotus eryngiiwhich was stored under 0.02 MPa. The cause of these abnormal conditions may be when the storage pressure was 0.02 MPa, the vacuum degree was higher, and a larger pressure difference was formed. The larger pressure difference caused some mechanical damage and physiological injury on Pleurotus eryngii fruit body. The cell structure was destroyed. And the normal metabolic pathway and related enzyme system were changed under the larger pressure difference

  18. 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...

  19. Differential and Reciprocal Regulation between Hypoxia-inducible Factor-α Subunits and Their Prolyl Hydroxylases in Pulmonary Arteries of Rat with Hypoxia-induced Hypertension

    Institute of Scientific and Technical Information of China (English)

    Yun-Rong CHEN; Ai-Guo DAI; Rui-Cheng HU; Yong-Liang JIANG

    2006-01-01

    Hypoxia-inducible factor (HIF)-α subunits (HIF-1 α, HIF-2α and HIF-3α), which play a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH), are regulated through posttranslational hydroxylation by their three prolyl hydroxylase domain-containing proteins (PHD1, PHD2 and PHD3). PHDs could also be regulated by HIF. But differential and reciprocal regulation between HIF-α and PHDs during the development of HPH remains unclear. To investigate this problem, a rat HPHmodel was established. Mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. HIF-1α and HIF-2α mRNA increasedslightly after 7 d of hypoxia, but HIF-3α increased significantly after 3 d of hypoxia. The protein expression levels of all three HIF-α were markedly upregulated after exposure to hypoxia. PHD2 mRNA and protein expression levels were upregulated after 3 d of hypoxia; PHD 1 protein declined after 14 d of hypoxia without significant mRNA changes. PHD3 mRNA and protein were markedly upregulated after 3 d of hypoxia, then the mRNA remained at a high level, but the protein declined after 14 d of hypoxia. In hypoxic animals, HIF-1α proteins negatively correlated with PHD2 proteins, whereas HIF-2α and HIF-3α proteins showed negative correlations with PHD3 and PHD1 proteins, respectively. All three HIF-α proteins were positively correlated with PHD2 and PHD3 mRNA. In the present study, HIF-α subunits and PHDs showed differential and reciprocal regulation, and this might play a key pathogenesis role in hypoxia-induced pulmonary hypertension.

  20. 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.

  1. The molecular basis of O2-sensing and hypoxia tolerance in pheochromocytoma cells.

    Science.gov (United States)

    Conrad, P W; Conforti, L; Kobayashi, S; Beitner-Johnson, D; Rust, R T; Yuan, Y; Kim, H W; Kim, R H; Seta, K; Millhorn, D E

    2001-02-01

    Hypoxia is a common environmental stimulus. However, very little is known about the mechanisms by which cells sense and respond to changes in oxygen. Our laboratory has utilized the PC12 cell line in order to study the biophysical and molecular response to hypoxia. The current review summarizes our results. We demonstrate that the O2-sensitive K(+) channel, Kv1.2, is present in PC12 cells and plays a critical role in the hypoxia-induced depolarization of PC12 cells. Previous studies have shown that PC12 cells secrete a variety of autocrine/paracrine factors, including dopamine, norepinephrine, and adenosine during hypoxia. We investigated the mechanisms by which adenosine modulates cell function and the effect of chronic hypoxia on this modulation. Finally, we present results identifying the mitogen- and stress-activated protein kinases (MAPKs and SAPKs) as hypoxia-regulated protein kinases. Specifically, we show that p38 and an isoform, p38gamma, are activated by hypoxia. In addition, our results demonstrate that the p42/p44 MAPK protein kinases are activated by hypoxia. We further show that p42/p44 MAPK is critical for the hypoxia-induced transactivation of endothelial PAS-domain protein 1 (EPAS1), a hypoxia-inducible transcription factor. Together, these results provide greater insight into the mechanisms by which cells sense and adapt to hypoxia. PMID:11207433

  2. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    International Nuclear Information System (INIS)

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential

  3. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

    2014-02-26

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

  4. 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.

  5. Hypoxia activated EGFR signaling induces epithelial to mesenchymal transition (EMT.

    Directory of Open Access Journals (Sweden)

    Ashish Misra

    Full Text Available Metastasis is a multi-step process which requires the conversion of polarized epithelial cells to mesenchymal cells, Epithelial-Mesenchymal Transition (EMT. EMT is essential during embryonic morphogenesis and has been implicated in the progression of primary tumors towards metastasis. Hypoxia is known to induce EMT; however the molecular mechanism is still poorly understood. Using the A431 epithelial cancer cell line, we show that cells grown under hypoxic conditions migrated faster than cells grown under normal oxygen environment. Cells grown under hypoxia showed reduced adhesion to the extracellular matrix (ECM probably due to reduced number of Vinculin patches. Growth under hypoxic conditions also led to down regulation of E-cadherin and up regulation of vimentin expression. The increased motility of cells grown under hypoxia could be due to redistribution of Rac1 to the plasma membrane as opposed to increased expression of Rac1. EGF (Epidermal Growth Factor is a known inducer of EMT and growth of A431 cells in the absence of oxygen led to increased expression of EGFR (EGF Receptor. Treatment of A431 cells with EGF led to reduced cell adhesion to ECM, increased cell motility and other EMT characteristics. Furthermore, this transition was blocked by the monoclonal antibody Cetuximab. Cetuximab also blocked the hypoxia-induced EMT suggesting that cell growth under hypoxic conditions led to activation of EGFR signaling and induction of EMT phenotype.

  6. 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.

  7. Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.

    Science.gov (United States)

    Selfridge, Andrew C; Cavadas, Miguel A S; Scholz, Carsten C; Campbell, Eric L; Welch, Lynn C; Lecuona, Emilia; Colgan, Sean P; Barrett, Kim E; Sporn, Peter H S; Sznajder, Jacob I; Cummins, Eoin P; Taylor, Cormac T

    2016-05-27

    Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated. PMID:27044749

  8. 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.

  9. Human skin hypoxia modulates cerebrovascular and autonomic functions.

    Science.gov (United States)

    Pucci, Olivia; Qualls, Clifford; Battisti-Charbonney, Anne; Balaban, Dahlia Y; Fisher, Joe A; Duffin, Jim; Appenzeller, Otto

    2012-01-01

    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. PMID:23056597

  10. Use of Satellite Remote Sensing to Improve Coastal Hypoxia Prediction

    Science.gov (United States)

    We describe the use of Giovanni satellite remote sensing products in the development and testing of a new modeling system that represents the processes leading to hypoxia (defined as water O2 concentration < 63 mmol m-3) on the Louisiana continental shelf (LCS). The modeling ...

  11. 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.

  12. 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.

  13. 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. PMID:26319559

  14. Modeling dissolved oxygen dynamics and coastal hypoxia: a review

    Directory of Open Access Journals (Sweden)

    M. A. Peña

    2009-09-01

    Full Text Available Hypoxia occurs in marine ecosystems throughout the world, influences biogeochemical cycles of elements and may have severe impacts on marine life. Hypoxia results from complex interactions between physical and biogeochemical processes, which can not be addressed by observations alone. In this paper, we review oxygen dynamical models that have been applied in studies of factors controlling coastal hypoxia and in predictions of future states. We also identify scientific issues that need further development and point out some of the major challenges. Over recent decades, substantial progress has been made in the development of oxygen dynamical models. Considerable progress has been made towards the parameterization of biogeochemical processes in the water column and sediments, such as the dynamic representation of nitrification-denitrification. Recent advances in three-dimensional coupled physical-ecological-biogeochemical models allow better representation of physical-biological interactions. Several types of modelling approaches, from simple to complex, have significantly contributed to improve our understanding of hypoxia. We discuss the applications of these models to the study of the effects of oxygen depletion on biogeochemical cycles, links between nutrient enrichment and hypoxia development, impacts of hypoxia on marine ecosystems and predictions of climate change responses. However, for some processes models are still crude. For example, current representations of organic matter transformations and remineralization are incomplete, as they are mostly based on empirical parameterizations at few locations. For most of these processes, the availability of validation data has been a limiting factor in model development. Another gap is that, in virtually all nutrient load models, efforts have focused on nutrient utilization and organic matter degradation, whereas three-dimensional mixing and advection have been less well represented. Explicit

  15. Upregulation of miR-203 and miR-210 affect growth and differentiation of keratinocytes after exposure to sulfur mustard in normoxia and hypoxia.

    Science.gov (United States)

    Deppe, Janina; Steinritz, Dirk; Santovito, Donato; Egea, Virginia; Schmidt, Annette; Weber, Christian; Ries, Christian

    2016-02-26

    Exposure of the skin to sulfur mustard (SM) results in long-term complications such as impaired tissue regeneration. Previous own studies in normal human epidermal keratinocytes (NHEK) treated with SM demonstrated reduced proliferation, premature differentiation and a restricted functionality of hypoxia-mediated signaling in the cells. Here, we investigated the involvement of microRNAs, miR-203 and miR-210, in these mechanisms. SM significantly upregulated the expression of miR-203 in NHEK when cultivated under normoxic and hypoxic conditions. SM had no effect on miR-210 under normoxia. However, miR-210 levels were greatly increased in NHEK when grown in hypoxia and further elevated upon exposure of the cells to SM. In normoxia and hypoxia, inhibition of miR-203 by transfection of NHEK with complementary oligonucleotides, anti-miR-203, attenuated the SM-induced impairment of metabolic activity and proliferation, and counteracted SM-promoted keratin-1 expression in these cells. Consistent ameliorating effects on dysregulated metabolic activity, proliferation and keratin-1 expression in SM-treated NHEK were obtained upon inhibition of miR-210 in these cells grown in hypoxia. Our findings provide evidence that miR-203 and miR-210 are key regulators in normal and SM-impaired keratinocyte functionality, and suggest potential usefulness of inhibitors against miR-203 and miR-210 for target-directed therapeutical intervention to improve re-epithelialization of SM-injured skin. PMID:26383628

  16. 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

  17. Phosphorylation dynamics of radixin in hypoxia-induced hepatocyte injury.

    Science.gov (United States)

    Suda, Jo; Rockey, Don C; Karvar, Serhan

    2015-02-15

    The most prominent ezrin-radixin-moesin protein in hepatocytes is radixin, which is localized primarily at the canalicular microvilli and appears to be important in regulation of cell polarity and in localizing the multidrug resistance-associated protein 2 (Mrp-2) function. Our aim was to investigate how hypoxia affects radixin distribution and Mrp-2 function. We created wild-type and mutant constructs (in adenoviral vectors), which were expressed in WIF-B cells. The cellular distribution of Mrp-2 and radixin was visualized by fluorescence microscopy, and a 5-chloromethylfluorescein diacetate (CMFDA) assay was used to measure Mrp-2 function. Under usual conditions, cells infected with wild-type radixin, nonphosphorylatable radixin-T564A, and radixin-T564D (active phospho-mimicking mutant) were found to be heavily expressed in canalicular membrane compartment vacuoles, typically colocalizing with Mrp-2. In contrast, after hypoxia for 24 h, both endogenous and overexpressed wild-type radixin and the radixin-T564A mutant were found to be translocated to the cytoplasmic space. However, distribution of the radixin-T564D mutant, which mimics constant phosphorylation, was remarkably different, being associated with canalicular membranes even in hypoxic conditions. This dominant-active construct also prevented dissociation of radixin from the plasma membrane. Hypoxia also led to Mrp-2 mislocalization and caused Mrp-2 to be dissociated from radixin; the radixin phospho-mimicking mutant (T564D) abrogated this effect of hypoxia. Finally, hypoxia diminished the secretory response (measured using the CMFDA assay) in WIF-B cells, and the dominant-active construct (radixin-T567D) rescued this phenotype. Taken collectively, these findings suggest that radixin regulates Mrp-2 localization and function in hepatocytes and is important in hypoxic liver injury. PMID:25501552

  18. 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

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Hyun-Joo Park

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

  1. 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).

  2. Hypoxia Inducible Factor-1 Alpha Correlates the Expression of Heme Oxygenase 1 Gene in Pulmonary Arteries of Rat with Hypoxia-induced Pulmonary Hypertension

    Institute of Scientific and Technical Information of China (English)

    Qi-Fang LI; Ai-Guo DAI

    2004-01-01

    To test the hypothesis that hypoxia inducible factor-1 alph (HIF-la) up-regulated theexpression ofheme oxygenase-1(HO-1) gene in pulmonary arteries of rats with hypoxia-induced pulmonaryhypertension, 8 male Wistar rats in each of 5 groups were exposed to hypoxia for 0, 3, 7, 14 or 21d, respectively.Mean pulmonary arterial pressure(mPAP), vessel morphometry and right ventricle hypertrophy index weremeasured. Lungs were inflation fixed for immunohistochemistry, in situ hybridization; frozen for latermeasurement of HO-1 enzyme activity, mPAP increased significantly after 7d of hypoxia [(18.4±0.4)mmHg, P<0.05], reaching its peak after 14d of hypoxia, then remained stable. Pulmonary artery remodelingbecame to develop significantly after 14d ofhypoxia. H1F-1α protein in control was poorly positive (0.05±0.01), but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterialtunica media, the levels of HIF-lα protein were markedly up-regulated after 3d and 7d of hypoxia(0.20±0.02; 0.22±0.02, P<0.05), then declined after 14d and 21d of hypoxia. HIF-1a mRNA stainingwas poorly positive in control, hypoxia for 3 and 7d, but enhanced significantly after 14d of hypoxia(0.20±0.02, P<0.05), then remained stable. HO-1 protein increased after 7d of hypoxia (0.10±0.01,P<0.05), reaching its peak after 14d ofhypoxia (0.21±0.02, P<0.05), then remained stable. HO-1 mRNAincreased after 3d of hypoxia, reaching its peak after 7d of hypoxia (0.17±0.01, P<0.05), then declined.Linear correlation analysis showed that HIF-la mRNA, HO-1 protein and mPAP were associatedwith pulmonary remodeling. HIF-1α protein (tunica intima) was conversely correlated with HIF-1a mRNA(r=0.921, P<0.01), HO-1 protein was conversely correlated with HIF-lα protein (tunica intima)(r=0.821, P<0.01). HIF-1α and HO-1 were both involved in the pathogenesis of hypoxia-induced pulmonaryhypertension in rat. Hypoxia inducible factor-1 alpha correlated the

  3. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    Energy Technology Data Exchange (ETDEWEB)

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-01-01

    In Section 1 of this first report we will describe the work we are doing to collect and analyze rock physics data for the purpose of modeling seismic attenuation from other measurable quantities such as porosity, water saturation, clay content and net stress. This work and other empirical methods to be presented later, will form the basis for ''Q pseudo-well modeling'' that is a key part of this project. In Section 2 of this report, we will show the fundamentals of a new method to extract Q, dispersion, and attenuation from field seismic data. The method is called Gabor-Morlet time-frequency decomposition. This technique has a number of advantages including greater stability and better time resolution than spectral ratio methods.

  4. 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.

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

    International Nuclear Information System (INIS)

    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

  6. 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

  7. Mechanisms of geometrical seismic attenuation

    Directory of Open Access Journals (Sweden)

    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. Development and pathological changes of neurovascular unit regulated by hypoxia response in the retina.

    Science.gov (United States)

    Kurihara, T

    2016-01-01

    Retina is a highly vascularized tissue with a high oxygen and metabolic demand receiving light located in the back of the eye. The development and the maintenance of the retinal vasculature are important to regulate the homeostasis in the tissue. α Subunits of hypoxia-inducible factor (HIF) are key molecules in hypoxia response inducing genes required for cell survival such as vascular endothelial growth factor under hypoxia. Neurons, glia, and vascular endothelium cells interdependently form neurovascular unit in the retina tightly regulated by hypoxia response via HIF expression. A corruption of the precise hypoxia response in the developmental or matured retinal tissue may lead congenital vascular anomalies or adult neovascular ocular diseases. To regulate hypoxia response through HIF activity would be an ideal therapeutic target for these vision-threatening eye diseases. PMID:27130417

  2. Hypoxia, Nitrogen, and Fisheries: Integrating Effects Across Local and Global Landscapes

    Science.gov (United States)

    Breitburg, Denise L.; Hondorp, Darryl W.; Davias, Lori A.; Diaz, Robert J.

    2009-01-01

    Anthropogenic nutrient enrichment and physical characteristics result in low dissolved oxygen concentrations (hypoxia) in estuaries and semienclosed seas throughout the world. Published research indicates that within and near oxygen-depleted waters, finfish and mobile macroinvertebrates experience negative effects that range from mortality to altered trophic interactions. Chronic exposure to hypoxia and fluctuating oxygen concentrations impair reproduction, immune responses, and growth. We present an analysis of hypoxia, nitrogen loadings, and fisheries landings in 30 estuaries and semienclosed seas worldwide. Our results suggest that hypoxia does not typically reduce systemwide fisheries landings below what would be predicted from nitrogen loadings, except where raw sewage is released or particularly sensitive species lose critical habitat. A number of compensatory mechanisms limit the translation of local-scale effects of hypoxia to the scale of the whole system. Hypoxia is, however, a serious environmental challenge that should be considered in fisheries management strategies and be a direct target of environmental restoration.

  3. 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.

  4. 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.

  5. Regulation of heme oxygenase expression by alcohol,hypoxia and oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Lisa; Nicole; Gerjevic; Jonathan; Pascal; Chaky; Duygu; Dee; Harrison-Findik

    2011-01-01

    AIM:To study the effect of both acute and chronic alcohol exposure on heme oxygenases(HOs) in the brain,liver and duodenum.METHODS:Wild-type C57BL/6 mice,heterozygous Sod2 knockout mice,which exhibit attenuated manganese superoxide dismutase activity,and liver-specific ARNT knockout mice were used to investigate the role of alcohol-induced oxidative stress and hypoxia.For acute alcohol exposure,ethanol was administered in the drinking water for 1 wk.Mice were pair-fed with regular or ethanol-containing Lieber De Carli liquid diets for 4 wk for chronic alcohol studies.HO expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting.RESULTS:Chronic alcohol exposure downregulated HO-1 expression in the brain but upregulated it in the duodenum of wild-type mice.It did not alter liver HO-1 expression,nor HO-2 expression in the brain,liver or duodenum.In contrast,acute alcohol exposure decreased both liver HO-1 and HO-2 expression,and HO-2 expression in the duodenum of wild-type mice.The decrease in liver HO-1 expression was abolished in ARNT+/-mice.Sod2+/-mice with acute alcohol exposure did not exhibit any changes in liver HO-1 and HO-2 expression or in brain HO-2 expression.However,alcohol inhibited brain HO-1 and duodenal HO-2 but increased duodenal HO-1 expression in Sod2+/-mice.Collectively,these findings indicate that acute and chronic alcohol exposure regulates HO expression in a tissue-specific manner.Chronic alcohol exposure alters brain and duodenal,but not liver HO expression.However,acute alcohol exposure inhibits liver HO-1 and HO-2,and also duodenal HO-2 expression.CONCLUSION:The inhibition of liver HO expression by acute alcohol-induced hypoxia may play a role in the early phases of alcoholic liver disease progression.

  6. Spinal Plasticity following Intermittent Hypoxia: Implications for Spinal Injury

    OpenAIRE

    Dale-Nagle, Erica A.; Hoffman, Michael S.; MacFarlane, Peter M.; Satriotomo, Irawan; Lovett-Barr, Mary Rachael; Vinit, Stéphane; Mitchell, Gordon S.

    2010-01-01

    Plasticity is a fundamental property of the neural system controlling breathing. One frequently studied model of respiratory plasticity is long-term facilitation of phrenic motor output (pLTF) following acute intermittent hypoxia (AIH). pLTF arises from spinal plasticity, increasing respiratory motor output through a mechanism that requires new synthesis of brain derived neurotrophic factor (BDNF), activation of its high affinity receptor, tropomyosin-related kinase B (TrkB) and extracellular...

  7. 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.

  8. Thioredoxin interacting protein inhibits hypoxia-inducible factor transcriptional activity

    OpenAIRE

    Farrell, Michael R; Rogers, Lynette K.; Liu, Yusen; Welty, Stephen E.; Tipple, Trent E.

    2010-01-01

    Vascular endothelial growth factor (VEGF) is required for proper lung development and is transcriptionally regulated in alveolar epithelial cells by hypoxia inducible factor (HIF). Previous findings in a newborn mouse model of bronchopulmonary dysplasia (BPD) suggest that thioredoxin interacting protein (Txnip) is a novel regulator of VEGF expression. The present studies were designed to test the hypothesis that Txnip negatively regulates VEGF through effects on HIF-mediated gene expression. ...

  9. Responding to hypoxia: lessons from a model cell line.

    Science.gov (United States)

    Seta, K A; Spicer, Z; Yuan, Y; Lu, G; Millhorn, D E

    2002-08-20

    Mammalian cells require a constant supply of oxygen to maintain adequate energy production, which is essential for maintaining normal function and for ensuring cell survival. Sustained hypoxia can result in cell death. It is, therefore, not surprising that sophisticated mechanisms have evolved that allow cells to adapt to hypoxia. "Oxygen-sensing" is a special phenotype that functions to detect changes in oxygen tension and to transduce this signal into organ system functions that enhance the delivery of oxygen to tissue in various organisms. Oxygen-sensing cells can be segregated into two distinct cell types: those that functionally depolarize (excitable) and those that do not functionally depolarize (nonexcitable) in response to reduced oxygen. Theoretically, excitable cells have all the same signaling capabilities as the nonexcitable cells, but the nonexcitable cells cannot have all the signaling capabilities as excitable cells. A number of signaling pathways have been identified that regulate gene expression during hypoxia. These include the Ca2+-calmodulin pathway, the 3'-5' adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, the p42 and p44 mitogen-activated protein kinase [(MAPK); also known as the extracellular signal-related kinase (ERK) for ERK1 and ERK2] pathway, the stress-activated protein kinase (SAPK; also known as p38 kinase) pathway, and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. In this review, we describe hypoxia-induced signaling in the model O2-sensing rat pheochromocytoma (PC12) cell line, the current level of understanding of the major signaling events that are activated by reduced O2, and how these signaling events lead to altered gene expression in both excitable and nonexcitable oxygen-sensing cells. PMID:12189251

  10. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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

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

    Science.gov (United States)

    Basaran, Kemal Erdem; Villongco, Michael; Ho, Baran; Ellis, Erika; Zarndt, Rachel; Antonova, Julie; Hopkins, Susan R; Powell, Frank L

    2016-01-01

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Does hypoxia play a role in infantile hemangioma?

    Science.gov (United States)

    de Jong, Sophie; Itinteang, Tinte; Withers, Aaron H J; Davis, Paul F; Tan, Swee T

    2016-05-01

    Infantile hemangioma (IH), the most common tumor of infancy, is characterized by rapid growth during infancy, followed by spontaneous involution over 5-10 years. Certain clinical observations have led to the suggestion that IH is triggered and maintained by hypoxia. We review the literature on the possible role of hypoxia in the etiology of IH, in particular, (1) the role of hypoxia inducible factor-1α (HIF-1α) and its downstream targets including GLUT-1 and VEGF; (2) the pathophysiological link between IH and retinopathy of prematurity; (3) hypoxic events in the early life including placental insufficiency, pre-eclampsia and low birthweight that have the potential to promote hypoxic stress; and (4) the evidence supporting the development of IH independent of HIF-1α. We also discuss these observations in the context of recent evidence of the crucial role of stem cells and the cytokines niche that governs their proliferation and inevitable differentiation, offering novel insights into the biology of IH. We propose that various triggers may simultaneously up-regulate HIF-1α, which is downstream of the renin-angiotensin system, specifically angiotensin II, which promotes production of HIF-1α. These developments shed light to the understanding of this enigmatic condition. PMID:26940670

  16. Genome-wide identification of hypoxia-induced enhancer regions

    Science.gov (United States)

    Preston, Jessica L.; Randel, Melissa A.; Johnson, Eric A.

    2015-01-01

    Here we present a genome-wide method for de novo identification of enhancer regions. This approach enables massively parallel empirical investigation of DNA sequences that mediate transcriptional activation and provides a platform for discovery of regulatory modules capable of driving context-specific gene expression. The method links fragmented genomic DNA to the transcription of randomer molecule identifiers and measures the functional enhancer activity of the library by massively parallel sequencing. We transfected a Drosophila melanogaster library into S2 cells in normoxia and hypoxia, and assayed 4,599,881 genomic DNA fragments in parallel. The locations of the enhancer regions strongly correlate with genes up-regulated after hypoxia and previously described enhancers. Novel enhancer regions were identified and integrated with RNAseq data and transcription factor motifs to describe the hypoxic response on a genome-wide basis as a complex regulatory network involving multiple stress-response pathways. This work provides a novel method for high-throughput assay of enhancer activity and the genome-scale identification of 31 hypoxia-activated enhancers in Drosophila. PMID:26713262

  17. IGFBP-3, hypoxia and TNF-{alpha} inhibit adiponectin transcription

    Energy Technology Data Exchange (ETDEWEB)

    Zappala, Giovanna, E-mail: zappalag@mail.nih.gov [Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States); Rechler, Matthew M. [Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States); Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States)

    2009-05-15

    The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-{gamma}, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-{gamma}-RXR-{alpha} heterodimers bound to PPAR-{gamma} response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-{alpha}, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-{alpha} inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-{gamma}2. Native IGFBP-3 can bind RXR-{alpha} and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-{alpha} did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-{alpha}, and that IGFBP-3 binding to RXR-{alpha} may be required for the observed inhibition.

  18. Polychaete Annelid Biomass Size Spectra: The Effects of Hypoxia Stress

    Directory of Open Access Journals (Sweden)

    Fangyuan Qu

    2015-01-01

    Full Text Available Quantitative benthic samples were taken during spring and summer at three locations on the Louisiana continental shelf from 2004 to 2012 to assess the influence of hypoxia on the mean sizes (wet weight of polychaete annelid worms. While the mean body size over the entire study of 64 samples was 3.99 ± 4.66 mg wet weight per individual, the mean ranged from 2.97 ± 2.87 mg during consistently hypoxic conditions (2 mg/L. The variations in size within assemblages were estimated from conventional biomass size spectra (BSS and normalized biomass size spectra (NBSS across a broad range of oxygen concentrations. The decline in size was due to the elimination of large species under hypoxic conditions (<2 mg/L, not a reduction in size within species. At “severe” levels of hypoxia (<1 mg/L, the smallest species also declined in abundance, whereas the ubiquitous “medium-sized” Paraprionospio pinnata flourished. These results suggest that there will be enhanced selection for small sizes and species with enlarged branchial palps such as those in P. pinnata if, as predicted, hypoxia becomes more commonplace in time and space worldwide.

  19. Hypoxia-inducible factor-1 in tumour angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yong-Hong Shi; Wei-Gang Fang

    2004-01-01

    Hypoxia-inducible factor-1 (HIF-1), composed of HIF-α and HIF-β subunits, is a heterodimeric transcriptional activator.In response to hypoxia, stimulation of growth factors, and activation of oncogenes as well as carcinogens, HIF-1α is overexpressed and/or activated and targets those genes which are required for angiogenesis, metabolic adaptation to low oxygen and promotes survival. HIF-1 is critical for both physiological and pathological processes. Several dozens of putative direct HIF-1 target genes have been identified on the basis of one or more cis-acting hypoxia-response elements that contain an HIF-1 binding site. A variety of regulators including growth factors, genetic alterations, stress activators, and some carcinogens have been documented for regulation of HIF-1 in which several signaling pathways are involved depending on the stimuli and cell types.Activation of HIF-1 in combination with activated signaling pathways and regulators is implicated in tumour progression and prognosis. This review presents a summary of the structure and function of HIF-1α, and correlation among specific regulators and their signaling pathways.

  20. Increased Neuronal Hypoxic Tolerance Induced by Repetitive Chemical Hypoxia

    Institute of Scientific and Technical Information of China (English)

    李红戈; 刘昌勤; 孙圣刚

    2002-01-01

    Summary: To investigate the effects of time interval and cumulative dosage of repetitive mild cellular hypoxia on shape of neurodegeneration and neuroprotection in mice, population spike amplitude (PSA) was measured during hypoxia and posthypoxic recovery in hippocampal slices from untreated control and mice pretreated in vivo with a single or repeatedly intraperitoneal injection of 3-nitropropi onate (3-NP). Posthypoxic recovery of PSA was dose-dependent in single pretreated slices, with maximal recovery on pretreatment attained with 20 mg/kg 3-NP (82±32%, P< 0. 01). Upon 5 and 9 treatments with 20 mg/kg 3-NP (dosage interval 3 days), PSA recovered to (38±9) % with the difference being not significant vs control group and (72±45) % with the difference being signif icant (P< 0. 05 to control, P<0.05 to 5 treatments), respectively. In contrast, with 2 days time interval, recovery after 5 and 9 treatments was (30±25) % and (16±14) %, respectively (without significant difference from control). Continued neuroprotection was also observed upon increase of dosage interval to 4 and 5 days. It was suggested that repetitive chemical hypoxia is a model for neu rodegenerative disease and continued neuroprotection depending on time interval between repetitive hypoxic episodes rather than cumulative dosage. At appropriate time intervals increased neuronal hy-poxic tolerance could be induced with number of hypoxic episodes.

  1. Hypoxia and tumors%低氧与肿瘤

    Institute of Scientific and Technical Information of China (English)

    孙恒; 李雪冰; 方靖

    2013-01-01

    Hypoxia occurs in solid tumors as a result of an inadequate supply of oxygen, due to rapid cell proliferation and inefficient vascular supply. Hypoxia induces expression of hypoxia-inducible factor a (HIF-a) that activates transcription of many genes, which may help tumors adapting to the environment of low oxygen. HIF-a plays a critical role in tumor cell proliferation, survival, metabolism, metastasis and angiogenesis. It is also related to inflammation and drug resistance. Therefore, HIF-a is becoming an important target for cancer therapy.%肿瘤细胞的快速生长使得肿瘤内部缺氧,导致低氧诱导因子HIF-α的积累.HIF-α可以引起多种基因的转录,使得肿瘤细胞能够耐受低氧环境.综述了肿瘤细胞感受和传导低氧信号的机制,并从肿瘤细胞增殖、凋亡、代谢、迁移、浸润、血管生成以及炎症和药物耐受等多方面论述了HIF-α在肿瘤发生发展中所发挥的重要作用.以HIF-α为靶点是治疗肿瘤的重要手段和方法.

  2. 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.

  3. Hypoxia induces no change in cutaneous thresholds for warmth and cold sensation

    OpenAIRE

    Malanda, U.L.; Reulen, J.P.H.; Saris, W. H. M.; van Marken Lichtenbelt, W. D.

    2008-01-01

    Hypoxia can affect perception of temperature stimuli by impeding thermoregulation at a neural level. Whether this impact on the thermoregulatory response is solely due to affected thermoregulation is not clear, since reaction time may also be affected by hypoxia. Therefore, we studied the effect of hypoxia on thermal perception thresholds for warmth and cold. Thermal perception thresholds were determined in 11 healthy overweight adult males using two methods for small nerve fibre functioning:...

  4. Role of hypoxia-inducible factor 1α in modulating cobalt-induced lung inflammation

    OpenAIRE

    Saini, Yogesh; Kim, Kyung Y.; Lewandowski, Ryan; Bramble, Lori A.; Harkema, Jack R.; LaPres, John J.

    2009-01-01

    Hypoxia plays an important role in development, cellular homeostasis, and pathological conditions, such as cancer and stroke. There is also growing evidence that hypoxia is an important modulator of the inflammatory process. Hypoxia-inducible factors (HIFs) are a family of proteins that regulate the cellular response to oxygen deficit, and loss of HIFs impairs inflammatory cell function. There is little known, however, about the role of epithelial-derived HIF signaling in modulating inflammat...

  5. 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.

    urgently increase their support to nutrient reduction projects, building on GEF’s experi- ence and leadership. Coastal hypoxia and its causes are multi-focal area issues. GEF-International Waters is the lead focal area but hypoxia also concerns... and single sector management such as in coordinating and ranking the sectoral and spatial priorities for interventions and comparing the cost effectiveness of different pollution reduc- tion options. Since coastal hypoxia typically involves large...

  6. Time-dependent effect of acute hypoxia on corticospinal excitability in healthy humans.

    OpenAIRE

    Rupp, Thomas; Jubeau, Marc; Wuyam, Bernard; Perrey, Stéphane; Levy, Patrick; Millet, Guillaume; Vergès, Samuel

    2012-01-01

    International audience Contradictory results regarding the effect of hypoxia on cortex excitability have been reported in healthy subjects, possibly depending on hypoxia exposure duration. We evaluated the effects of 1- and 3-h hypoxia on motor corticospinal excitability, intracortical inhibition, and cortical voluntary activation (VA) using transcranial magnetic stimulation (TMS). TMS to the quadriceps cortex area and femoral nerve electrical stimulations were performed in 14 healthy subj...

  7. Hypoxia and Human Genome Stability: Downregulation of BRCA2 Expression in Breast Cancer Cell Lines

    OpenAIRE

    Daniele Fanale; Viviana Bazan; Stefano Caruso; Marta Castiglia; Giuseppe Bronte; Christian Rolfo; Giuseppe Cicero; Antonio Russo

    2013-01-01

    Previously, it has been reported that hypoxia causes increased mutagenesis and alteration in DNA repair mechanisms. In 2005, an interesting study showed that hypoxia-induced decreases in BRCA1 expression and the consequent suppression of homologous recombination may lead to genetic instability. However, nothing is yet known about the involvement of BRCA2 in hypoxic conditions in breast cancer. Initially, a cell proliferation assay allowed us to hypothesize that hypoxia could negatively regula...

  8. Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle

    OpenAIRE

    Hartman, William; Helan, Martin; Smelter, Dan; Sathish, Venkatachalem; Thompson, Michael; Pabelick, Christina M.; Johnson, Bruce; Y S Prakash

    2015-01-01

    Background Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in hu...

  9. Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types.

    Directory of Open Access Journals (Sweden)

    Audrey Sermeus

    Full Text Available Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIM(EL. BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and -independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.

  10. 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...

  11. 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...... important prognostic information and may help identify potential hypoxia circumventing and targeting strategies. This review summarizes current knowledge on HIF regulation and function in tumour cells and discusses the aspects of using companion animals as comparative spontaneous cancer models. Spontaneous...

  12. Clematichinenoside (AR) Attenuates Hypoxia/Reoxygenation-Induced H9c2 Cardiomyocyte Apoptosis via a Mitochondria-Mediated Signaling Pathway

    OpenAIRE

    Haiyan Ding; Rong Han; Xueshan Chen; Weirong Fang; Meng Liu; Xuemei Wang; Qin Wei; Nandani Darshika Kodithuwakku; Yunman Li

    2016-01-01

    Mitochondria-mediated cardiomyocyte apoptosis is involved in myocardial ischemia/reperfusion (MI/R) injury. Clematichinenoside (AR) is a triterpenoid saponin isolated from the roots of Clematis chinensis with antioxidant and anti-inflammatory cardioprotection effects against MI/R injury, yet the anti-apoptotic effect and underlying mechanisms of AR in MI/R injury remain unclear. We hypothesize that AR may improve mitochondrial function to inhibit MI/R-induced cardiomyocyte apoptosis. In this ...

  13. Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans

    DEFF Research Database (Denmark)

    Møller, P; Loft, S; Lundby, C;

    2001-01-01

    The present study investigated the effect of a single bout of exhaustive exercise on the generation of DNA strand breaks and oxidative DNA damage under normal conditions and at high-altitude hypoxia (4559 meters for 3 days). Twelve healthy subjects performed a maximal bicycle exercise test...... oxygen species, generated by leakage of the mitochondrial respiration or during a hypoxia-induced inflammation. Furthermore, the presence of DNA strand breaks may play an important role in maintaining hypoxia-induced inflammation processes. Hypoxia seems to deplete the antioxidant system of its capacity...

  14. Exercise and DHA prevent the negative effects of hypoxia on EEG and nerve conduction velocity.

    Science.gov (United States)

    Erken, Haydar Ali; Erken, Gülten; Colak, Rıdvan; Genç, Osman

    2013-12-01

    It is known that hypoxia has a negative effect on nervous system functions, but exercise and DHA (docosahexaenoic acid) have positive effect. In this study, it was investigated whether exercise and/or DHA can prevent the effects of hypoxia on EEG and nerve conduction velocity (NCV). 35 adult Wistar albino male rats were divided into five groups (n=7): control (C), hypoxia (H), hypoxia and exercise (HE), hypoxia and DHA (HD), and hypoxia and exercise and DHA (HED) groups. During the 28-day hypoxia exposure, the HE and HED groups of rats were exercised (0% incline, 30 m/min speed, 20 min/day, 5 days a week). In addition, DHA (36 mg/kg/day) was given by oral gavage to rats in the HD and HED groups. While EEG records were taken before and after the experimental period, NCV records were taken after the experimental period from anesthetized rats. Data were analyzed by paired t-test, one-way ANOVA, and post hoc Tukey test. In this study, it was show