[Near-Drowning with Good Outcome after ECMO-Therapy and Therapeutic Hypothermia Despite 20 Minutes of Anoxia and 16 Hours of Hypoxia].

Science.gov (United States)

Stachon, Peter; Kalbhenn, Johannes; Walterspacher, Stephan; Bode, Christoph; Staudacher, Dawid

2017-04-01

Introduction  Drowning with submersion over 10 minutes is associated with a high mortality. Here, we present a case, in which a good neurological outcome was achieved after interdisciplinary, intensive care therapy despite submersion of 20 minutes followed by 16 hours of hypoxia. History  A 19 year old man drowned in fresh-water. After 20 minutes submersion he was localized and salvaged from 8 meters depth and primarily resuscitated successfully after 10 minutes. Within the next hour, there condition worsened by respiratory deterioration due to a massive capillary leak syndrome in addition to a disseminated intravascular coagulation. Treatment  This made implantation of a veno-venous ECMO (extracorporeal membrane oxygenation) therapy necessary. Despite intensive care medicine including extracorporeal therapy a sufficient oxygenation (arterial pO 2 > 60 mmHg) was reached only 16 hours after the drowning. Clinical Course  During this time the patient was treated with a mild therapeutic hypothermia for cerebral protection. Despite the prolonged hypoxia, ECMO could be removed five days after the drowning and the patient was extubated after another five days without significant neurological deficits. Conclusion  Despite submersion of 20 minutes followed by prolonged hypoxia, a good neurological outcome could be achieved in our patient. This case suggests, that tolerance of hypoxia is possibly underestimated after drowning. © Georg Thieme Verlag KG Stuttgart · New York.

Guide to good practice in radiation protection training

International Nuclear Information System (INIS)

Johnson, N.; Schenley, C.; Smith, A.; Weseman, M.

1988-10-01

This set of guidelines applies to radiation protection training programs for all Department of Energy (DOE) contractors, subcontractors, and visitors to DOE contractor facilities. It is to be used as a self-evaluation tool by DOE contractors as they develop and evaluate their training programs. This document is based on good practice guidelines used by a variety of different facilities both within and outside of the DOE contractor system. Good practices are not requirements; they are guidelines that contractors should use as they develop and conduct training programs. The applicability of the contents of the Guide to Good Practice in Radiation Protection Training depends upon each DOE facility's scope and need for radiation safety training. Although the focus of this document is radiation protection training, it is important that the process by which training is developed and implemented be discussed. Therefore, the first section presents guidelines for performance-based training and ideas to be considered regarding the structure and documentation of the training function

Effects of Repeated-Sprint Training in Hypoxia on Sea-Level Performance: A Meta-Analysis.

Science.gov (United States)

Brocherie, Franck; Girard, Olivier; Faiss, Raphaël; Millet, Grégoire P

2017-08-01

Repeated-sprint training in hypoxia (RSH) is a recent intervention regarding which numerous studies have reported effects on sea-level physical performance outcomes that are debated. No previous study has performed a meta-analysis of the effects of RSH. We systematically reviewed the literature and meta-analyzed the effects of RSH versus repeated-sprint training in normoxia (RSN) on key components of sea-level physical performance, i.e., best and mean (all sprint) performance during repeated-sprint exercise and aerobic capacity (i.e., maximal oxygen uptake [[Formula: see text

Interval training by normobaric hypoxia accelerates the reinnervation of musculus extensor digitorum longus in mice

DEFF Research Database (Denmark)

Vardya, Irina; (Vard'ya); Mospanova, Svetlana V.

2000-01-01

Dokl Biol Sci. 2000 Mar-Apr;371:112-4. Interval training by normobaric hypoxia accelerates the reinnervation of musculus extensor digitorum longus in mice. Vard'ya IV , Mospanova SV , Portnov VV , Balezina OP , Koshelev VB . Department of Human and Animal Physiology, Faculty of Biology, Moscow St...... State University, Russia. PMID: 10833635 [PubMed - indexed for MEDLINE] Udgivelsesdato: 2000...

Neuroendocrine Responses and Body Composition Changes Following Resistance Training Under Normobaric Hypoxia

Directory of Open Access Journals (Sweden)

Chycki Jakub

2016-12-01

Full Text Available The aim of the present study was to evaluate the effects of a 6 week resistance training protocol under hypoxic conditions (FiO2 = 12.9%, 4000 m on muscle hypertrophy. The project included 12 resistance trained male subjects, randomly divided into two experimental groups. Group 1 (n = 6; age 21 ± 2.4 years; body height [BH] 178.8 ± 7.3 cm; body mass [BM] 80.6 ± 12.3 kg and group 2 (n = 6; age 22 ± 1.5 years; BH 177.8 ± 3.7cm; BM 81.1 ± 7.5 kg. Each group performed resistance exercises alternately under normoxic and hypoxic conditions (4000 m for 6 weeks. All subjects followed a training protocol that comprised two training sessions per week at an exercise intensity of 70% of 1RM; each training session consisted of eight sets of 10 repetitions of the bench press and barbell squat, with 3 min rest periods. The results indicated that strength training in normobaric hypoxia caused a significant increase in BM (p < 0.01 and fat free mass (FFM (p < 0.05 in both groups. Additionally, a significant increase (p < 0.05 was observed in IGF-1 concentrations at rest after 6 weeks of hypoxic resistance training in both groups. The results of this study allow to conclude that resistance training (6 weeks under normobaric hypoxic conditions induces greater muscle hypertrophy compared to training in normoxic conditions.

Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

Science.gov (United States)

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

2011-01-01

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

Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia

Czech Academy of Sciences Publication Activity Database

Alánová, Petra; Chytilová, Anna; Neckář, Jan; Hrdlička, Jaroslav; Míčová, P.; Holzerová, Kristýna; Hlaváčková, Markéta; Macháčková, Kristýna; Papoušek, František; Vašinová, Jana; Benák, Daniel; Nováková, Olga; Kolář, František

2017-01-01

Roč. 122, č. 6 (2017), s. 1452-1461 ISSN 8750-7587 R&D Projects: GA ČR(CZ) GA13-10267S; GA ČR(CZ) GJ16-12420Y; GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : chronic hypoxia * exercise training * cardioprotection * cytokines * antioxidants Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery OBOR OECD: Physiology (including cytology) Impact factor: 3.351, year: 2016

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

Directory of Open Access Journals (Sweden)

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.

Effects of intermittent hypoxia on running economy.

Science.gov (United States)

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

2010-09-01

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

Increased Hypoxic Dose After Training at Low Altitude with 9h Per Night at 3000m Normobaric Hypoxia.

Science.gov (United States)

Carr, Amelia J; Saunders, Philo U; Vallance, Brent S; Garvican-Lewis, Laura A; Gore, Christopher J

2015-12-01

This study examined effects of low altitude training and a live-high: train-low protocol (combining both natural and simulated modalities) on haemoglobin mass (Hbmass), maximum oxygen consumption (VO2max), time to exhaustion, and submaximal exercise measures. Eighteen elite-level race-walkers were assigned to one of two experimental groups; lowHH (low Hypobaric Hypoxia: continuous exposure to 1380 m for 21 consecutive days; n = 10) or a combined low altitude training and nightly Normobaric Hypoxia (lowHH+NHnight: living and training at 1380 m, plus 9 h.night(-1) at a simulated altitude of 3000 m using hypoxic tents; n = 8). A control group (CON; n = 10) lived and trained at 600 m. Measurement of Hbmass, time to exhaustion and VO2max was performed before and after the training intervention. Paired samples t-tests were used to assess absolute and percentage change pre and post-test differences within groups, and differences between groups were assessed using a one-way ANOVA with least significant difference post-hoc testing. Statistical significance was tested at p altitude (1380 m) combined with sleeping in altitude tents (3000 m) as one effective alternative to traditional altitude training methods, which can improve Hbmass. Key pointsIn some countries, it may not be possible to perform classical altitude training effectively, due to the low elevation at altitude training venues. An additional hypoxic stimulus can be provided by simulating higher altitudes overnight, using altitude tents.Three weeks of combined (living and training at 1380 m) and simulated altitude exposure (at 3000 m) can improve haemoglobin mass by over 3% in comparison to control values, and can also improve time to exhaustion by ~9% in comparison to baseline.We recommend that, in the context of an altitude training camp at low altitudes (~1400 m) the addition of a relatively short exposure to simulated altitudes of 3000 m can elicit physiological and performance benefits, without compromise to

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation.

Science.gov (United States)

Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

2017-03-03

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO 2 , 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

Effects of U.S. Navy Diver Training on Physiological Parameters, Time of Useful Consciousness and Cognitive Performance During Periods of Normobaric Hypoxia

Science.gov (United States)

2014-04-01

TRAINING ON PHYSIOLOGICAL PARAMETERS, TIME OF USEFULL CONSCIOUSNESS, AND COGNITIVE PERFORMANCE DURING PERIODS OF NORMOBARIC HYPOXIA...Sato, Y. Watanabe, "Time of Usefull Consciousness Determination in Aircrew Members with Rerference to Prior Altitude Chamber Experience and Age

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

Science.gov (United States)

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

2016-02-01

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. Copyright © 2016 the American Physiological Society.

Resistance Training Using Different Hypoxic Training Strategies: a Basis for Hypertrophy and Muscle Power Development

OpenAIRE

Feriche, Bel?n; Garc?a-Ramos, Amador; Morales-Artacho, Antonio J.; Padial, Paulino

2017-01-01

The possible muscular strength, hypertrophy, and muscle power benefits of resistance training under environmental conditions of hypoxia are currently being investigated. Nowadays, resistance training in hypoxia constitutes a promising new training strategy for strength and muscle gains. The main mechanisms responsible for these effects seem to be related to increased metabolite accumulation due to hypoxia. However, no data are reported in the literature to describe and compare the efficacy of...

'When psychology and economics meet: Relational goods in training groups

Directory of Open Access Journals (Sweden)

Alessandra Di Caccamo

2014-09-01

Full Text Available The development of the concept of relational goods is an innovation in the economy as opposed to the predominant instrumental logic and the ultimate aim of achieving profit. By facilitating the process of remodeling and reconfiguration the modalities of entering into a relationship, and allowing a new connection between different dimension of one's family, relational and cultural experience, median training groups are a place of choice for developing relational good in different contexts.Keywords: Relational good; Median training group; Social well-being

Increased Hypoxic Dose After Training at Low Altitude with 9h Per Night at 3000m Normobaric Hypoxia

Directory of Open Access Journals (Sweden)

Amelia J. Carr, Philo U. Saunders, Brent S. Vallance, Laura A. Garvican-Lewis, Christopher J. Gore

2015-12-01

Full Text Available This study examined effects of low altitude training and a live-high: train-low protocol (combining both natural and simulated modalities on haemoglobin mass (Hbmass, maximum oxygen consumption (VO2max, time to exhaustion, and submaximal exercise measures. Eighteen elite-level race-walkers were assigned to one of two experimental groups; lowHH (low Hypobaric Hypoxia: continuous exposure to 1380 m for 21 consecutive days; n = 10 or a combined low altitude training and nightly Normobaric Hypoxia (lowHH+NHnight: living and training at 1380 m, plus 9 h.night-1 at a simulated altitude of 3000 m using hypoxic tents; n = 8. A control group (CON; n = 10 lived and trained at 600 m. Measurement of Hbmass, time to exhaustion and VO2max was performed before and after the training intervention. Paired samples t-tests were used to assess absolute and percentage change pre and post-test differences within groups, and differences between groups were assessed using a one-way ANOVA with least significant difference post-hoc testing. Statistical significance was tested at p < 0.05. There was a 3.7% increase in Hbmass in lowHH+NHnight compared with CON (p = 0.02. In comparison to baseline, Hbmass increased by 1.2% (±1.4% in the lowHH group, 2.6% (±1.8% in lowHH+NHnight, and there was a decrease of 0.9% (±4.9% in CON. VO2max increased by ~4% within both experimental conditions but was not significantly greater than the 1% increase in CON. There was a ~9% difference in pre and post-intervention values in time to exhaustion after lowHH+NH-night (p = 0.03 and a ~8% pre to post-intervention difference (p = 0.006 after lowHH only. We recommend low altitude (1380 m combined with sleeping in altitude tents (3000 m as one effective alternative to traditional altitude training methods, which can improve Hbmass.

Hypoxia targeting copper complexes

International Nuclear Information System (INIS)

Dearling, J.L.

1998-11-01

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

Guide to good practices for on-the-job training

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-04-01

Training programs at DOE facilities should prepare personnel to safely and efficiently operate and maintain the facilities in accordance with DOE requirements. This guide presents good practices for a systematic approach to on-the-job training (OJT) and OJT programs and should be used in conjunction with DOE Training Program Handbook: A Systematic Approach to Training, and with the DOE Handbook entitled Alternative Systematic Approaches to Training to develop performance-based OJT programs. DOE contractors may also use this guide to modify existing OJT programs that do not meet the systematic approach to training (SAT) objectives.

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

International Nuclear Information System (INIS)

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

1997-01-01

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

Classical altitude training.

Science.gov (United States)

Friedmann-Bette, B

2008-08-01

For more than 40 years, the effects of classical altitude training on sea-level performance have been the subject of many scientific investigations in individual endurance sports. To our knowledge, no studies have been performed in team sports like football. Two well-controlled studies showed that living and training at an altitude of >or=1800-2700 m for 3-4 weeks is superior to equivalent training at sea level in well-trained athletes. Most of the controlled studies with elite athletes did not reveal such an effect. However, the results of some uncontrolled studies indicate that sea-level performance might be enhanced after altitude training also in elite athletes. Whether hypoxia provides an additional stimulus for muscular adaptation, when training is performed with equal intensity compared with sea-level training is not known. There is some evidence for an augmentation of total hemoglobin mass after classical altitude training with duration >or=3 weeks at an altitude >or=2000 m due to altitude acclimatization. Considerable individual variation is observed in the erythropoietic response to hypoxia and in the hypoxia-induced reduction of aerobic performance capacity during training at altitude, both of which are thought to contribute to inter-individual variation in the improvement of sea-level performance after altitude training.

Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

Energy Technology Data Exchange (ETDEWEB)

Saxena, Saurabh [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India); Shukla, Dhananjay [Department of Biotechnology, Gitam University, Gandhi Nagar, Rushikonda, Visakhapatnam-530 045 Andhra Pradesh (India); Bansal, Anju, E-mail: anjubansaldipas@gmail.com [Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054 (India)

2012-11-01

High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl{sub 2}), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl{sub 2} supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl{sub 2} supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl{sub 2} supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl{sub 2} for 15 days along with training. ► Co

Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

International Nuclear Information System (INIS)

Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

2012-01-01

High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl 2 ), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl 2 supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl 2 supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl 2 supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl 2 for 15 days along with training. ► CoCl 2 supplementation

Guide to good practices for on-the-job training

Energy Technology Data Exchange (ETDEWEB)

1992-07-01

The purpose of the Department of Energy (DOE) Guide to Good Practices for On-the-Job Training (OJT) is to provide DOE contractor organizations with information that can be used to modify existing programs or to develop new programs. This guide replaces the Guide to Good Practices for On-the-Job Training that was distributed to DOE and DOE contractors in 1987. DOE contractors should not feel obligated to adopt all parts of this guide. Rather, they can use the information in this guide to develop programs that apply to their facility. This guide can be used as an aid in the design and development of a facility's OJT programs and to assist the instructors who conduct OJT and performance tests in the areas of facility operations, maintenance, and technical supports.

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.

Guide to good practices for training and qualification of instructors. DOE handbook

Energy Technology Data Exchange (ETDEWEB)

NONE

1996-03-01

Purpose of this guide is to provide contractor training organizations with information that can be used to verify the adquacy and/or modify existing instructor training programs, or to develop new training programs. It contains good practices for the training and qualification of technical instructors and instructional technologists at DOE reactor and non-reactor nuclear facilities. It addresses the content of initial and continuing instructor training programs, evaluation of instructor training programs, and maintenance of instructor training records.

Predicting tumor hypoxia in non-small cell lung cancer by combining CT, FDG PET and dynamic contrast-enhanced CT.

Science.gov (United States)

Even, Aniek J G; Reymen, Bart; La Fontaine, Matthew D; Das, Marco; Jochems, Arthur; Mottaghy, Felix M; Belderbos, José S A; De Ruysscher, Dirk; Lambin, Philippe; van Elmpt, Wouter

2017-11-01

Most solid tumors contain inadequately oxygenated (i.e., hypoxic) regions, which tend to be more aggressive and treatment resistant. Hypoxia PET allows visualization of hypoxia and may enable treatment adaptation. However, hypoxia PET imaging is expensive, time-consuming and not widely available. We aimed to predict hypoxia levels in non-small cell lung cancer (NSCLC) using more easily available imaging modalities: FDG-PET/CT and dynamic contrast-enhanced CT (DCE-CT). For 34 NSCLC patients, included in two clinical trials, hypoxia HX4-PET/CT, planning FDG-PET/CT and DCE-CT scans were acquired before radiotherapy. Scans were non-rigidly registered to the planning CT. Tumor blood flow (BF) and blood volume (BV) were calculated by kinetic analysis of DCE-CT images. Within the gross tumor volume, independent clusters, i.e., supervoxels, were created based on FDG-PET/CT. For each supervoxel, tumor-to-background ratios (TBR) were calculated (median SUV/aorta SUV mean ) for HX4-PET/CT and supervoxel features (median, SD, entropy) for the other modalities. Two random forest models (cross-validated: 10 folds, five repeats) were trained to predict the hypoxia TBR; one based on CT, FDG, BF and BV, and one with only CT and FDG features. Patients were split in a training (trial NCT01024829) and independent test set (trial NCT01210378). For each patient, predicted, and observed hypoxic volumes (HV) (TBR > 1.2) were compared. Fifteen patients (3291 supervoxels) were used for training and 19 patients (1502 supervoxels) for testing. The model with all features (RMSE training: 0.19 ± 0.01, test: 0.27) outperformed the model with only CT and FDG-PET features (RMSE training: 0.20 ± 0.01, test: 0.29). All tumors of the test set were correctly classified as normoxic or hypoxic (HV > 1 cm 3 ) by the best performing model. We created a data-driven methodology to predict hypoxia levels and hypoxia spatial patterns using CT, FDG-PET and DCE-CT features in NSCLC. The

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

International Nuclear Information System (INIS)

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

2011-01-01

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

Altitude and endurance training.

Science.gov (United States)

Rusko, Heikki K; Tikkanen, Heikki O; Peltonen, Juha E

2004-10-01

The benefits of living and training at altitude (HiHi) for an improved altitude performance of athletes are clear, but controlled studies for an improved sea-level performance are controversial. The reasons for not having a positive effect of HiHi include: (1) the acclimatization effect may have been insufficient for elite athletes to stimulate an increase in red cell mass/haemoglobin mass because of too low an altitude (altitude training period (training effect at altitude may have been compromised due to insufficient training stimuli for enhancing the function of the neuromuscular and cardiovascular systems; and (3) enhanced stress with possible overtraining symptoms and an increased frequency of infections. Moreover, the effects of hypoxia in the brain may influence both training intensity and physiological responses during training at altitude. Thus, interrupting hypoxic exposure by training in normoxia may be a key factor in avoiding or minimizing the noxious effects that are known to occur in chronic hypoxia. When comparing HiHi and HiLo (living high and training low), it is obvious that both can induce a positive acclimatization effect and increase the oxygen transport capacity of blood, at least in 'responders', if certain prerequisites are met. The minimum dose to attain a haematological acclimatization effect is > 12 h a day for at least 3 weeks at an altitude or simulated altitude of 2100-2500 m. Exposure to hypoxia appears to have some positive transfer effects on subsequent training in normoxia during and after HiLo. The increased oxygen transport capacity of blood allows training at higher intensity during and after HiLo in subsequent normoxia, thereby increasing the potential to improve some neuromuscular and cardiovascular determinants of endurance performance. The effects of hypoxic training and intermittent short-term severe hypoxia at rest are not yet clear and they require further study.

High-Intensity Interval Training in Normobaric Hypoxia Improves Cardiorespiratory Fitness in Overweight Chinese Young Women.

Science.gov (United States)

Kong, Zhaowei; Shi, Qingde; Nie, Jinlei; Tong, Tomas K; Song, Lili; Yi, Longyan; Hu, Yang

2017-01-01

Previous studies have investigated the effects of high-intensity interval training (HIIT) on cardiorespiratory fitness and body composition in overweight populations. However, the additive effect of HIIT and hypoxia on health parameters is not clear. This study compared the effects of HIIT under hypoxic conditions on cardiometabolic function with that under normoxia in overweight Chinese young women. Methods: A double-blind randomized controlled experimental design was applied. Twenty-four sedentary overweight Chinese young women (weight: 68.8 ± 7.0 kg, BMI: 25.8 ± 2.3 kg·m -2 ) participated in the HIIT under either normoxia (NORM, n = 13, PIO 2 : 150 mmHg, FIO 2 : 0.21) or normobaric hypoxia (HYP, n = 11, PIO 2 : 117 mmHg, FIO 2 : 0.15) for 5 weeks. HIIT was composed of 60 repetitions of 8 s maximal cycling effort interspersed with 12-s recovery per day, for 4 days per week. Cardiorespiratory fitness [peak oxygen uptake ([Formula: see text]O 2peak ), and peak oxygen pulse (peak O 2 pulse)], serum lipid profile [triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)], and body composition (regional and whole-body), were assessed at pre- and post-intervention during the days beyond the self-reported menstrual phase of the participants. Habitual physical activity and diary behavior were maintained during the intervention period. Results: With similar daily energy intake and physical activity, the increases in [Formula: see text]O 2peak [NORM: 0.26 ± 0.37 L·min -1 (+11.8%) vs. HYP: 0.54 ± 0.34 L·min -1 (+26.1%)] and peak O 2 pulse (NORM: +13.4% vs. HYP: +25.9%) for HYP were twice-larger than for NORM ( p body composition or serum fasting leptin were observed in either group. Conclusion: 5-wk of HIIT improved cardiorespiratory fitness and blood lipids in overweight Chinese young females, while the additive effect of the HIIT under normobaric hypoxia solely enhanced

The ventilatory response to hypoxia: how much is good for a mountaineer?

OpenAIRE

Milledge, J. S.

1987-01-01

Methods for measuring the ventilatory response to hypoxia (HVR) are reviewed. The criteria for success as a high altitude mountaineer are defined as freedom from acute mountain sickness (AMS) and ability to perform well at extreme altitude. The evidence for a brisk HVR being protective against AMS and associated with successful high altitude performance is reviewed. The contrary evidence of blunted HVR in high altitude residence and some elite climbers is discussed. The effect of a brisk HVR ...

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

Directory of Open Access Journals (Sweden)

Julie E Gleason

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

IGF-1 attenuates hypoxia-induced atrophy but inhibits myoglobin expression in C2C12 skeletal muscle myotubes

NARCIS (Netherlands)

Peters, Eva L.; van der Linde, Sandra M.; Vogel, Ilse S.P.; Haroon, Mohammad; Offringa, Carla; de Wit, Gerard M.J.; Koolwijk, Pieter; van der Laarse, Willem J.; Jaspers, Richard T.

2017-01-01

Chronic hypoxia is associated with muscle wasting and decreased oxidative capacity. By contrast, training under hypoxia may enhance hypertrophy and increase oxidative capacity as well as oxygen transport to the mitochondria, by increasing myoglobin (Mb) expression. The latter may be a feasible

Similar inflammatory responses following sprint interval training performed in hypoxia and normoxia

Directory of Open Access Journals (Sweden)

Alan James Richardson

2016-08-01

Full Text Available Sprint interval training (SIT is an efficient intervention capable of improving aerobic capacity and exercise performance. This experiment aimed to determine differences in training adaptations and the inflammatory responses following 2 weeks of SIT (30s maximal work, 4 min recovery; 4-7 repetitions performed in normoxia or hypoxia. Forty-two untrained participants [(mean ± SD, age 21 ±1 yrs, body mass 72.1 ±11.4 kg and height 173 ±10 cm] were equally and randomly assigned to one of three groups; control (CONT; no training, n = 14, normoxic (NORM; SIT in FiO2: 0.21, n = 14 and normobaric hypoxic (HYP; SIT in FiO2: 0.15, n = 14. Participants completed a V̇O2peak test, a time to exhaustion (TTE trial (power = 80% V̇O2peak and had haematological [haemoglobin (Hb, haematocrit (Hct] and inflammatory markers [interleukin-6 (IL-6, tumor necrosis factor-α (TNFα] measured in a resting state, pre and post SIT. V̇O2peak (mL.kg-1.min-1 improved in HYP (+11.9% and NORM (+9.8%, but not CON (+0.9%. Similarly TTE improved in HYP (+32.2% and NORM (+33.0%, but not CON (+3.4% whilst the power at the anaerobic threshold (AT; W.kg-1 also improved in HYP (+13.3% and NORM (+8.0%, but not CON (-0.3%. AT (mL.kg-1.min-1 improved in HYP (+9.5%, but not NORM (+5% or CON (-0.3%. No between group change occurred in 30 s sprint performance or Hb and Hct. IL-6 increased in HYP (+17.4% and NORM (+20.1%, but not CON (+1.2% respectively. TNF-α increased in HYP (+10.8% NORM (+12.9% and CON (+3.4%.SIT in HYP and NORM increased VO2peak, power at AT and TTE performance in untrained individuals, improvements in AT occurred only when SIT was performed in HYP. Increases in IL-6 and TNFα reflect a training induced inflammatory response to SIT; hypoxic conditions do not exacerbate this.

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...

Normobaric hypoxia increases the growth hormone response to maximal resistance exercise in trained men.

Science.gov (United States)

Filopoulos, Dean; Cormack, Stuart J; Whyte, Douglas G

2017-08-01

This study examined the effect of hypoxia on growth hormone (GH) release during an acute bout of high-intensity, low-volume resistance exercise. Using a single-blinded, randomised crossover design, 16 resistance-trained males completed two resistance exercise sessions in normobaric hypoxia (HYP; inspiratory oxygen fraction, (FiO 2 ) 0.12, arterial oxygen saturation (SpO 2 ) 82 ± 2%) and normoxia (NOR; FiO 2 0.21, SpO 2 98 ± 0%). Each session consisted of five sets of three repetitions of 45° leg press and bench press at 85% of one repetition maximum. Heart rate, SpO 2 , and electromyographic activity (EMG) of the vastus lateralis muscle were measured throughout the protocol. Serum lactate and GH levels were determined pre-exposure, and at 5, 15, 30 and 60 min post-exercise. Differences in mean and integrated EMG between HYP and NOR treatments were unclear. However, there was an important increase in the peak levels and area under the curve of both lactate (HYP 5.8 ± 1.8 v NOR 3.9 ± 1.1 mmol.L -1 and HYP 138.7 ± 33.1 v NOR 105.8 ± 20.8 min.mmol.L -1 ) and GH (HYP 4.4 ± 3.1 v NOR 2.1 ± 2.5 ng.mL -1 and HYP 117.7 ± 86.9 v NOR 72.9 ± 85.3 min.ng.mL -1 ) in response to HYP. These results suggest that performing high-intensity resistance exercise in a hypoxic environment may provide a beneficial endocrine response without compromising the neuromuscular activation required for maximal strength development.

Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses

Directory of Open Access Journals (Sweden)

Tatiana V. Serebrovskaya

2015-05-01

Full Text Available Intermittent hypoxia often occurs in early infancy in both preterm and term infants and especially at 36 to 44 weeks postmenstrual age. These episodes of intermittent hypoxia could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of intermittent hypoxia on development, behavior, academic achievement and cognition in children with sleep apnea syndrome. It remains uncertain the exact causative relationship between the neurocognitive and behavioral morbidities and intermittent hypoxia and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate intermittent hypoxia conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g. hypercapnia, polycythemia, in order to prevent or reduce its harmful consequences, while maximize its potential utility as an effective therapeutic tool in pediatric patients.

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...

Guide to good practices for on-the-job training. DOE guideline

Energy Technology Data Exchange (ETDEWEB)

1992-07-01

The purpose of the Department of Energy (DOE) Guide to Good Practices for On-the-Job Training (OJT) is to provide DOE contractor organizations with information that can be used to modify existing programs or to develop new programs. This guide replaces the Guide to Good Practices for On-the-Job Training that was distributed to DOE and DOE contractors in 1987. DOE contractors should not feel obligated to adopt all parts of this guide. Rather, they can use the information in this guide to develop programs that apply to their facility. This guide can be used as an aid in the design and development of a facility`s OJT programs and to assist the instructors who conduct OJT and performance tests in the areas of facility operations, maintenance, and technical supports.

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

Science.gov (United States)

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

2014-01-01

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

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.

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

Science.gov (United States)

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

2013-01-01

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

Altitude training improves glycemic control.

Science.gov (United States)

Chen, Shu-Man; Lin, Hsueh-Yi; Kuo, Chia-Hua

2013-08-31

Under altitude hypoxia condition, energy reliance on anaerobic glycolysis increases to compensate the shortfall caused by reduced fatty acid oxidation. Short-term moderate altitude exposure plus endurance physical activity has been found to improve glucose tolerance (not fasting glucose) in humans, which is associated with the improvement in the whole-body insulin sensitivity. However, most of people cannot accommodate high altitude exposure above 4500 M due to acute mountain sickness and insulin resistance. There is a wide variation among individuals in response to the altitude challenge. In particular, the improvement in glucose tolerance and insulin sensitivity by prolonged altitude hiking activity was not apparent in those individuals with low baseline dehydroepiandrosterone sulfate (DHEA-S) concentration. In rats, exercise training recovery under prolonged hypoxia exposure (14-15% oxygen, 8 h per day for 6 weeks) can also improve insulin sensitivity, secondary to an effective suppression of adiposity. After prolonged hypoxia training, obese abnormality in upregulated baseline levels of AMP-activated protein kinase (AMPK) and AS160 phosphorylation in skeletal muscle can be reversed. In humans, moderate hypoxia increases postprandial blood distribution towards skeletal muscle during a training recovery. This physiological response plays a role in the redistribution of fuel storage among important energy storage sites and may explain its potent effect on the favorable change in body composition. Altitude training can exert strong impact on our metabolic system, and has the potential to be designed as a non-pharmacological or recreational intervention regimen for correcting metabolic syndromes.

DOE handbook: Guide to good practices for training and qualification of maintenance personnel

International Nuclear Information System (INIS)

1996-03-01

The purpose of this Handbook is to provide contractor training organizations with information that can be used to verify the adequacy of and/or modify existing maintenance training programs, or to develop new training programs. This guide, used in conjunction with facility-specific job analyses, provides a framework for training and qualification programs for maintenance personnel at DOE reactor and nonreactor nuclear facilities. Recommendations for qualification are made in four areas: education, experience, physical attributes, and training. The functional positions of maintenance mechanic, electrician, and instrumentation and control technician are covered by this guide. Sufficient common knowledge and skills were found to include the three disciplines in one guide to good practices. Contents include: qualifications; on-the-job training; trainee evaluation; continuing training; training effectiveness evaluation; and program records. Appendices are included which relate to: administrative training; industrial safety training; fundamentals training; tools and equipment training; facility systems and component knowledge training; facility systems and component skills training; and specialized skills training

DOE handbook: Guide to good practices for training and qualification of maintenance personnel

Energy Technology Data Exchange (ETDEWEB)

NONE

1996-03-01

The purpose of this Handbook is to provide contractor training organizations with information that can be used to verify the adequacy of and/or modify existing maintenance training programs, or to develop new training programs. This guide, used in conjunction with facility-specific job analyses, provides a framework for training and qualification programs for maintenance personnel at DOE reactor and nonreactor nuclear facilities. Recommendations for qualification are made in four areas: education, experience, physical attributes, and training. The functional positions of maintenance mechanic, electrician, and instrumentation and control technician are covered by this guide. Sufficient common knowledge and skills were found to include the three disciplines in one guide to good practices. Contents include: qualifications; on-the-job training; trainee evaluation; continuing training; training effectiveness evaluation; and program records. Appendices are included which relate to: administrative training; industrial safety training; fundamentals training; tools and equipment training; facility systems and component knowledge training; facility systems and component skills training; and specialized skills training.

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

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

Directory of Open Access Journals (Sweden)

Mozhgan Jahani

2017-11-01

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

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

International Nuclear Information System (INIS)

Lundby, Carsten; Pilegaard, Henriette; Hall, Gerrit van; Sander, Mikael; Calbet, Jose; Loft, Steffen; Moeller, Peter

2003-01-01

Recent research suggests that high-altitude hypoxia may serve as a model for prolonged oxidative stress in healthy humans. In this study, we investigated the consequences of prolonged high-altitude hypoxia on the basal level of oxidative damage to nuclear DNA in muscle cells, a major oxygen-consuming tissue. Muscle biopsies from seven healthy humans were obtained at sea level and after 2 and 8 weeks of hypoxia at 4100 m.a.s.l. We found increased levels of strand breaks and endonuclease III-sensitive sites after 2 weeks of hypoxia, whereas oxidative DNA damage detected by formamidopyrimidine DNA glycosylase (FPG) protein was unaltered. The expression of 8-oxoguanine DNA glycosylase 1 (OGG1), determined by quantitative RT-PCR of mRNA levels did not significantly change during high-altitude hypoxia, although the data could not exclude a minor upregulation. The expression of heme oxygenase-1 (HO-1) was unaltered by prolonged hypoxia, in accordance with the notion that HO-1 is an acute stress response protein. In conclusion, our data indicate high-altitude hypoxia may serve as a good model for oxidative stress and that antioxidant genes are not upregulated in muscle tissue by prolonged hypoxia despite increased generation of oxidative DNA damage

Transport and handling of dangerous goods. Training of persons in charge of vehicles or vessels carrying dangerous goods by road or by inland waterways (Dangerous Goods 1979 No.1)

International Nuclear Information System (INIS)

1979-01-01

This Order supplements the Regulations of 15 April 1945 on the transport of dangerous goods by rail, land and inland waterways. It deals with the training of persons in charge of vehicles or boats carrying dangerous goods by road or by inland waterways. It refers in particular to transport of radioactive materials. (NEA) [fr

GOOD PRACTICES REGARDING PRESCHOOL AND PRIMARY SCHOOL TEACHERS` INITIAL TRAINING

Directory of Open Access Journals (Sweden)

Gabriela V. KELEMEN

2013-11-01

Full Text Available The training of future preschool and primary school teachers at a high quality level is a main goal of our institution and all our efforts are channelled towards fulfilling it. Being a teacher is a science, a science based on competences acquired while attending well-structured lectures that mingle theoretical knowledge with practical assignments. Students acquire knowledge, abilities and develop field related competences during initial training but three years of study are not enough. The Law of Education regulates the following amendment: in order for a teacher to be well trained to meet the requirements of the third millennium it is necessary for him/her to continue the training in level II i.e. master degree, which provides additional competences. In this article we discuss a master programme developed within an European project that offers educational training according to the requirements of a high quality training both practical and theoretical. The components of the Master programme entitled Psychopedagogy of early education and young schooling containa curriculum adjusted to the requirements of a competitive higher education, the courses and seminars are the result of a thorough analysis of different educational models that have been implemented in other European countries. Currently, we are at the end of the first year and we want to share the good practices obtained so far.

A Novel, Inexpensive Method to Monitor, Record, and Analyze Breathing Behavior During Normobaric Hypoxia Generated by the Reduced Oxygen Breathing Device.

Science.gov (United States)

Temme, Leonard A; St Onge, Paul; Adams, Mark; Still, David L; Statz, Jonathan K; Williams, Steven T

2017-03-01

Since hypoxia remains one of the most important physiological hazards the aviation environment poses, military aviators are trained to recognize symptoms of hypoxia in order to implement appropriate safety procedures and countermeasures when hypoxia occurs. A widely used commercial instrument for hypoxia training, demonstration, and research is the Reduced Oxygen Breathing Device (ROBD). Here we describe a novel, inexpensive method to use the ROBD's breathing loop pressure (BLP) to measure respiration rate, a critically important response parameter for hypoxia. The ROBD can be controlled by a computer to export several variables including BLP, via the ROBD's RS232 port. An archived database was reanalyzed to assess the BLP data. New instrumentation added independent measures of respiration and expired oxygen and carbon dioxide; these measures were integrated with the ROBD output. Analysis of the archived data showed that the BLP reflected realistic breathing patterns. The new instrumentation integrated well with the ROBD, and independently supported the potential of the BLP as a valid measure of respiration. The ROBD's BLP data may provide a basis for a reliable, sensitive measure of respiration that is available at no additional cost. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

Migraine induced by hypoxia

DEFF Research Database (Denmark)

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

2016-01-01

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

ORTHO-LBNP: A new apparatus for assessing autocontrol mechanisms of the heart-vessel system in pilots undergoing training in conditions of ischemic hypoxia and orthostatic stress

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Truszczynski, Olaf; Skibniewski, Franciszek; Dziuda, Lukasz; Gacek, Adam; Krej, Mariusz; Sobotnicki, Aleksander; Rajchel, Jan; Bylinka, Marek; Burek, Michal

The authors present a new system for examining the behaviour of the human body and cerebral circulation in conditions of ischemic hypoxia and orthostatic stress that can cause orthostatic hypotension. Ischemic hypoxia affects mainly pilots of highly manoeuvrable aircraft, where long-lasting G forces not seldom reach 6-8 +Gz and can exceed the gravitational acceleration by ten times or more. Additionally, pilots are subjected to orthostatic hypotension in which abnormally low blood pressure is caused by pressure adjustment disorder and decreased stroke volume when changing body position rapidly. For several decades, these effects have been deeply investigated using human centrifuges or lower body negative pressure (LBNP) chambers. The latter method involves significantly less financial resources to carry out experiments and training, whereas the effects exerted on pilots, and the results of the training can be comparable. A group of researchers from the Military Institute of Aviation Medicine, Warszawa, Poland, and the Institute of Medical Technology and Equipment ITAM, Zabrze, Poland, are developing the innovative ORTHO-LBNP device based on the cradle principle and the LBNP method. The system will be implemented in a modern programme for training cadets of the Polish Air Force Academy, Dęblin, Poland. Together with other equipment such as a high-G centrifuge, pressure chambers, flight and spatial disorientation simulators as well as gymnastic training equipment for pilots (GTEP), the ORTHO-LBNP apparatus will be an element of the selection system of candidates for aviation. It is expected that the experimental studies will result in developing new indicators providing an objective assessment, whether examined persons possess the traits necessary for performing tasks related to the job of a pilot. It is highly probable that those indicators can be incorporated into routine checks for pilots, which in turn, can lead to improving the safety of flight operations and

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

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Pei Wang

2013-09-01

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

Modulation of mitochondrial biomarkers by intermittent hypobaric hypoxia and aerobic exercise after eccentric exercise in trained rats.

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Rizo-Roca, David; Ríos-Kristjánsson, Juan Gabriel; Núñez-Espinosa, Cristian; Santos-Alves, Estela; Magalhães, José; Ascensão, António; Pagès, Teresa; Viscor, Ginés; Torrella, Joan Ramon

2017-07-01

Unaccustomed eccentric contractions induce muscle damage, calcium homeostasis disruption, and mitochondrial alterations. Since exercise and hypoxia are known to modulate mitochondrial function, we aimed to analyze the effects on eccentric exercise-induced muscle damage (EEIMD) in trained rats using 2 recovery protocols based on: (i) intermittent hypobaric hypoxia (IHH) and (ii) IHH followed by exercise. The expression of biomarkers related to mitochondrial biogenesis, dynamics, oxidative stress, and bioenergetics was evaluated. Soleus muscles were excised before (CTRL) and 1, 3, 7, and 14 days after an EEIMD protocol. The following treatments were applied 1 day after the EEIMD: passive normobaric recovery (PNR), 4 h daily exposure to passive IHH at 4000 m (PHR) or IHH exposure followed by aerobic exercise (AHR). Citrate synthase activity was reduced at 7 and 14 days after application of the EEIMD protocol. However, this reduction was attenuated in AHR rats at day 14. PGC-1α and Sirt3 and TOM20 levels had decreased after 1 and 3 days, but the AHR group exhibited increased expression of these proteins, as well as of Tfam, by the end of the protocol. Mfn2 greatly reduced during the first 72 h, but returned to basal levels passively. At day 14, AHR rats had higher levels of Mfn2, OPA1, and Drp1 than PNR animals. Both groups exposed to IHH showed a lower p66shc(ser 36 )/p66shc ratio than PNR animals, as well as higher complex IV subunit I and ANT levels. These results suggest that IHH positively modulates key mitochondrial aspects after EEIMD, especially when combined with aerobic exercise.

Altitud y deportes de equipo: métodos tradicionales desafiados por un entrenamiento innovador y específico en hipoxia. [Altitude and team sports: traditional methods challenged by innovative sport-specific training in hypoxia].

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Franck Brocherie

2016-10-01

level but train under hypoxic conditions, has gained unprecedented popularity. A thorough analysis of studies including IHT, however, leads to strikingly poor benefits for sea-level performance improvement, compared to the same training method performed in normoxia. Despite positive molecular adaptations observed after various IHT modalities, the characteristics of optimal training stimulus in hypoxia are still unclear and their functional translation in term of whole-body performance enhancement is minimal. To overcome some of the inherent limitations of IHT (lower workload due to hypoxia, recent studies have successfully investigated a new training method based on the repetition of short sprints with incomplete recoveries in hypoxia; named RSH. Additionally, the growing scientific interest on the practical application of hypoxic training legitimizes the development of innovative technologies serving athletes in a sport-specific setting. The aims of the present review are therefore threefold. First, to critically analyze the results of the studies involving high-intensity exercises performed in hypoxia for sea-level performance enhancement by differentiating IHT and RSH. Second, to discuss the potential mechanisms underpinning their effectiveness and their inherent limitations. Third, to present the potentials benefits of using new technological innovation (i.e., the mobile inflatable simulated hypoxic system which will undoubtedly contribute to the understanding advancement of hypoxia-induced physiological adaptations by conducting relevant research in the most sport-specific ecological test setting.

Exercise attenuates intermittent hypoxia-induced cardiac fibrosis associated with sodium-hydrogen exchanger-1 in rats

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Tsung-I Chen

2016-10-01

Full Text Available Purpose: To investigate the role of sodium–hydrogen exchanger-1 (NHE-1 and exercise training on intermittent hypoxia-induced cardiac fibrosis in obstructive sleep apnea (OSA, using an animal model mimicking the intermittent hypoxia of OSA. Methods: Eight-week-old male Sprague–Dawley rats were randomly assigned to control (CON, intermittent hypoxia (IH, exercise (EXE or IH combined with exercise (IHEXE groups. These groups were randomly assigned to subgroups receiving either a vehicle or the NHE-1 inhibitor cariporide. The EXE and IHEXE rats underwent exercise training on an animal treadmill for 10 weeks (5 days/week, 60 minutes/day, 24–30 m/minute, 2–10% grade. The IH and IHEXE rats were exposed to 14 days of IH (30 seconds of hypoxia - nadir of 2-6% O2 - followed by 45 seconds of normoxia for 8 hours/day. At the end of 10 weeks, rats were sacrificed and then hearts were removed to determine the myocardial levels of fibrosis index, oxidative stress, antioxidant capacity and NHE-1 activation. Results: Compared to the CON rats, IH induced higher cardiac fibrosis, lower myocardial catalase and superoxidative dismutase activities, higher myocardial lipid and protein peroxidation and higher NHE-1 activation (p < 0.05 for each, which were all abolished by cariporide. Compared to the IH rats, lower cardiac fibrosis, higher myocardial antioxidant capacity, lower myocardial lipid and protein peroxidation and lower NHE-1 activation were found in the IHEXE rats (p < 0.05 for each. Conclusion: IH-induced cardiac fibrosis was associated with NHE-1 hyperactivity. However, exercise training and cariporide exerted an inhibitory effect to prevent myocardial NHE-1 hyperactivity, which contributed to reduced IH-induced cardiac fibrosis. Therefore, NHE-1 plays a critical role in the effect of exercise on IH-induced increased cardiac fibrosis.

Hypoxia Decreases Invasin-Mediated Yersinia enterocolitica Internalization into Caco-2 Cells.

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Zeitouni, Nathalie E; Dersch, Petra; Naim, Hassan Y; von Köckritz-Blickwede, Maren

2016-01-01

Yersinia enterocolitica is a major cause of human yersiniosis, with enterocolitis being a typical manifestation. These bacteria can cross the intestinal mucosa, and invade eukaryotic cells by binding to host β1 integrins, a process mediated by the bacterial effector protein invasin. This study examines the role of hypoxia on the internalization of Y. enterocolitica into intestinal epithelial cells, since the gastrointestinal tract has been shown to be physiologically deficient in oxygen levels (hypoxic), especially in cases of infection and inflammation. We show that hypoxic pre-incubation of Caco-2 cells resulted in significantly decreased bacterial internalization compared to cells grown under normoxia. This phenotype was absent after functionally blocking host β1 integrins as well as upon infection with an invasin-deficient Y. enterocolitica strain. Furthermore, downstream phosphorylation of the focal adhesion kinase was also reduced under hypoxia after infection. In good correlation to these data, cells grown under hypoxia showed decreased protein levels of β1 integrins at the apical cell surface whereas the total protein level of the hypoxia inducible factor (HIF-1) alpha was elevated. Furthermore, treatment of cells with the HIF-1 α stabilizer dimethyloxalylglycine (DMOG) also reduced invasion and decreased β1 integrin protein levels compared to control cells, indicating a potential role for HIF-1α in this process. These results suggest that hypoxia decreases invasin-integrin-mediated internalization of Y. enterocolitica into intestinal epithelial cells by reducing cell surface localization of host β1 integrins.

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

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Bishop, Tammie; Ratcliffe, Peter J

2014-01-01

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

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

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Vaupel, Peter; Mayer, Arnulf

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

A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

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Fardin Paolo

2010-07-01

Full Text Available Abstract Background Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Results We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification. Conclusions Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.

Hypoxia, Oxidative Stress and Fat

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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.

Prediction of Critical Power and W' in Hypoxia: Application to Work-Balance Modelling.

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Townsend, Nathan E; Nichols, David S; Skiba, Philip F; Racinais, Sebastien; Périard, Julien D

2017-01-01

Purpose: Develop a prediction equation for critical power (CP) and work above CP (W') in hypoxia for use in the work-balance ([Formula: see text]) model. Methods: Nine trained male cyclists completed cycling time trials (TT; 12, 7, and 3 min) to determine CP and W' at five altitudes (250, 1,250, 2,250, 3,250, and 4,250 m). Least squares regression was used to predict CP and W' at altitude. A high-intensity intermittent test (HIIT) was performed at 250 and 2,250 m. Actual and predicted CP and W' were used to compute W' during HIIT using differential ([Formula: see text]) and integral ([Formula: see text]) forms of the [Formula: see text] model. Results: CP decreased at altitude ( P equations for CP and W' developed in this study are suitable for use with the [Formula: see text] model in acute hypoxia. This enables the application of [Formula: see text] modelling to training prescription and competition analysis at altitude.

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...

Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain.

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Lavie, Lena

2015-04-01

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is linked with increased reactive oxygen species/reactive nitrogen species (ROS/RNS) and oxidative stress, which adversely affect the associated cardio-/cerebro-vascular disease in OSA. Yet, animal and a small number of human studies support activation of cardio-/cerebro-protective mechanisms as well. ROS/RNS are intricate and multifaceted molecules with multiple functions. At low-moderate concentrations ROS/RNS are considered "good", by regulating vital cellular functions. At higher levels, they are considered "bad" by promoting oxidative stress and damaging vital macromolecules through ischemia and reperfusion (I/R) injury. Subsequently, ROS/RNS can get "ugly" by eliciting sterile inflammation and a multitude of deadly pathologies. What makes ROS/RNS good, bad, or ugly? A dynamic interplay between a large number of factors determines the outcomes. These include the types of ROS/RNS produced, their quantity, duration, frequency, intracellular localization, micro-environmental antioxidants, as well as the genetic make-up and life style related variables. This review presents the currently available data on redox biology in physiological/pathophysiological conditions and in OSA/IH, in order to better understand the apparently contradictory findings on damage vs. repair. These findings are discussed within the context of the prevailing views on I/R associated ROS/RNS, and their potential implications to OSA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of repetitive training at low altitude on erythropoiesis in 400 and 800 m runners.

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Frese, F; Friedmann-Bette, B

2010-06-01

Classical altitude training can cause an increase in total hemoglobin mass (THM) if a minimum "dose of hypoxia" is reached (altitude >or=2,000 m, >or=3 weeks). We wanted to find out if repetitive exposure to mild hypoxia during living and training at low altitude (training camps at low altitude interspersed by 3 weeks of sea-level training and at the same time points in a control group (CG) of 5 well-trained runners. EPO, sTfR and ferritin were also repeatedly measured during the altitude training camps. Repeated measures ANOVA revealed significant increases in EPO- and sTfR-levels during both training camps and a significant decrease in ferritin indicating enhanced erythropoietic stimulation during living and training at low altitude. Furthermore, significant augmentation of THM by 5.1% occurred in the course of the 2 altitude training camps. In conclusion, repetitive living and training at low altitude leads to a hypoxia-induced increase in erythropoietic stimulation in elite 400 m and 800 m runners and, apparently, might also cause a consecutive augmentation of THM.

Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome.

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González-Muniesa, P; Lopez-Pascual, A; de Andrés, J; Lasa, A; Portillo, M P; Arós, F; Durán, J; Egea, C J; Martinez, J A

2015-09-01

Strategies designed to reduce adiposity and cardiovascular-accompanying manifestations have been based on nutritional interventions conjointly with physical activity programs. The aim of this 13-week study was to investigate the putative benefits associated to hypoxia plus exercise on weight loss and relevant metabolic and cardiorespiratory variables, when prescribed to obese subjects with sleep apnea syndrome following dietary advice. The participants were randomly distributed in the following three groups: control, normoxia, and hypoxia. All the subjects received dietary advice while, additionally, normoxia group was trained under normal oxygen concentration and Hypoxia group under hypoxic conditions. There was a statistically significant decrease in fat-free mass (Kg) and water (%) on the control compared to normoxia group (p hypoxia compared to control group (p hypoxia group showed some specific benefits concerning appetite and cardiometabolic-related measurements as exertion time and diastolic blood pressure, with a therapeutical potential.

Developmental Hypoxia Has Negligible Effects on Long-Term Hypoxia Tolerance and Aerobic Metabolism of Atlantic Salmon (Salmo salar).

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Wood, Andrew T; Clark, Timothy D; Andrewartha, Sarah J; Elliott, Nicholas G; Frappell, Peter B

Exposure to developmental hypoxia can have long-term impacts on the physiological performance of fish because of irreversible plasticity. Wild and captive-reared Atlantic salmon (Salmo salar) can be exposed to hypoxic conditions during development and continue to experience fluctuating oxygen levels as juveniles and adults. Here, we examine whether developmental hypoxia impacts subsequent hypoxia tolerance and aerobic performance of Atlantic salmon. Individuals at 8°C were exposed to 50% (hypoxia) or 100% (normoxia) dissolved oxygen (DO) saturation (as percent of air saturation) from fertilization for ∼100 d (800 degree days) and then raised in normoxic conditions for a further 15 mo. At 18 mo after fertilization, aerobic scope was calculated in normoxia (100% DO) and acute (18 h) hypoxia (50% DO) from the difference between the minimum and maximum oxygen consumption rates ([Formula: see text] and [Formula: see text], respectively) at 10°C. Hypoxia tolerance was determined as the DO at which loss of equilibrium (LOE) occurred in a constantly decreasing DO environment. There was no difference in [Formula: see text], [Formula: see text], or aerobic scope between fish raised in hypoxia or normoxia. There was some evidence that hypoxia tolerance was lower (higher DO at LOE) in hypoxia-raised fish compared with those raised in normoxia, but the magnitude of the effect was small (12.52% DO vs. 11.73% DO at LOE). Acute hypoxia significantly reduced aerobic scope by reducing [Formula: see text], while [Formula: see text] remained unchanged. Interestingly, acute hypoxia uncovered individual-level relationships between DO at LOE and [Formula: see text], [Formula: see text], and aerobic scope. We discuss our findings in the context of developmental trajectories and the role of aerobic performance in hypoxia tolerance.

Contractile Activity Is Necessary to Trigger Intermittent Hypobaric Hypoxia-Induced Fiber Size and Vascular Adaptations in Skeletal Muscle

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David Rizo-Roca

2018-05-01

Full Text Available Altitude training has become increasingly popular in recent decades. Its central and peripheral effects are well-described; however, few studies have analyzed the effects of intermittent hypobaric hypoxia (IHH alone on skeletal muscle morphofunctionality. Here, we studied the effects of IHH on different myofiber morphofunctional parameters, investigating whether contractile activity is required to elicit hypoxia-induced adaptations in trained rats. Eighteen male Sprague-Dawley rats were trained 1 month and then divided into three groups: (1 rats in normobaria (trained normobaric inactive, TNI; (2 rats subjected daily to a 4-h exposure to hypobaric hypoxia equivalent to 4,000 m (trained hypobaric inactive, THI; and (3 rats subjected daily to a 4-h exposure to hypobaric hypoxia just before performing light exercise (trained hypobaric active, THA. After 2 weeks, the tibialis anterior muscle (TA was excised. Muscle cross-sections were stained for: (1 succinate dehydrogenase to identify oxidative metabolism; (2 myosin-ATPase to identify slow- and fast-twitch fibers; and (3 endothelial-ATPase to stain capillaries. Fibers were classified as slow oxidative (SO, fast oxidative glycolytic (FOG, fast intermediate glycolytic (FIG or fast glycolytic (FG and the following parameters were measured: fiber cross-sectional area (FCSA, number of capillaries per fiber (NCF, NCF per 1,000 μm2 of FCSA (CCA, fiber and capillary density (FD and CD, and the ratio between CD and FD (C/F. THI rats did not exhibit significant changes in most of the parameters, while THA animals showed reduced fiber size. Compared to TNI rats, FOG fibers from the lateral/medial fields, as well as FIG and FG fibers from the lateral region, had smaller FCSA in THA rats. Moreover, THA rats had increased NCF in FG fibers from all fields, in medial and posterior FIG fibers and in posterior FOG fibers. All fiber types from the three analyzed regions (except the posterior FG fibers displayed a

Coastal hypoxia and sediment biogeochemistry

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J. J. Middelburg

2009-07-01

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

Managing Human Factors Related Risks. The Advanced Training Model in Dangerous Goods Transport on Roads

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Jelizaveta Janno

2018-06-01

Full Text Available This paper studies the methodological essence of dangerous goods (DG training courses for drivers and dangerous goods safety advisers (DGSA. The aim of the research is to advance existing teacher-centered course model in Estonia with learner-centered methods that best suit specific objectives and meet expected learning outcomes, as well as to improve DG training model with the integrated use of interactive teaching methods. The paper presents a qualitative development research strategy based on studies regarding ADR regulations training courses in Estonia as well as on the analysis of teaching methods applied in the professional training of adults. The data is collected in two steps: firstly by implementing questionnaires for consignors/ consignees, freight forwarders carrier companies and drivers, secondly during in-depth interviews/ focus group meeting with DG regulations training companies’ providers. Implementing methodology of qualitative comparison analysis (QCA combination of best suitable teaching methods is identified. After following in-depth interviews and performing a focus group, these combinations are further used as input for developing existing course model with integrated use of blended learning alternatives, where digital media meets with traditional classroom meth-ods. Results of this research contribute coming up with interactive methodological approach within ADR regulations training courses that meet the best trainees’ expectations and fulfills the risk management aim.

Hypoxia triggers short term potentiation of phrenic motoneuron discharge after chronic cervical spinal cord injury

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Lee, Kun-Ze; Sandhu, Milapjit S.; Dougherty, Brendan J.; Reier, Paul J.; Fuller, David D.

2014-01-01

Repeated exposure to hypoxia can induce spinal neuroplasticity as well as respiratory and somatic motor recovery after spinal cord injury (SCI). The purpose of the present study was to define the capacity for a single bout of hypoxia to trigger short-term plasticity in phrenic output after cervical SCI, and to determine the phrenic motoneuron (PhrMN) bursting and recruitment patterns underlying the response. Hypoxia-induced short term potentiation (STP) of phrenic motor output was quantified in anesthetized rats 11 wks following lateral spinal hemisection at C2 (C2Hx). A 3-min hypoxic episode (12–14% O2) always triggered STP of inspiratory burst amplitude, the magnitude of which was greater in phrenic bursting ipsilateral vs. contralateral to C2Hx. We next determined if STP could be evoked in recruited (silent) PhrMNs ipsilateral to C2Hx. Individual PhrMN action potentials were recorded during and following hypoxia using a “single fiber” approach. STP of bursting activity did not occur in cells initiating bursting at inspiratory onset, but was robust in recruited PhrMNs as well as previously active cells initiating bursting later in the inspiratory effort. We conclude that following chronic C2Hx, a single bout of hypoxia triggers recruitment of PhrMNs in the ipsilateral spinal cord with bursting that persists beyond the hypoxic exposure. The results provide further support for the use of short bouts of hypoxia as a neurorehabilitative training modality following SCI. PMID:25448009

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

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

2018-01-23

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

Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor.

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Knowles, Helen J; Schaefer, Karl-Ludwig; Dirksen, Uta; Athanasou, Nicholas A

2010-07-16

Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. HIF-1alpha and HIF-2alpha immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. 17/56 Ewing's tumours were HIF-1alpha-positive, 15 HIF-2alpha-positive and 10 positive for HIF-1alpha and HIF-2alpha. Expression of HIF-1alpha and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1alpha and HIF-2alpha in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2alpha in Ewing's. Downstream transcription was HIF-1alpha-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by >or= 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Co-localisation of HIF-1alpha and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas.

Exercise Improves Mood State in Normobaric Hypoxia.

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

2015-11-01

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

Hepcidin: A Critical Regulator Of Iron Metabolism During Hypoxia

Science.gov (United States)

2011-01-01

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

[Physiological aspects of altitude training and the use of altitude simulators].

Science.gov (United States)

Ranković, Goran; Radovanović, Dragan

2005-01-01

Altitude training in various forms is widely practiced by athletes and coaches in an attempt to improve sea level endurance. Training at high altitude may improve performance at sea level through altitude acclimatisation, which improves oxygen transport and/or utilisation, or through hypoxia, which intensifies the training stimulus. This basic physiological aspect allows three training modalities: live high and train high (classic high-altitude training), live low and train high (training through hypoxia), and live high and train low (the new trend). In an effort to reduce the financial and logistical challenges of travelling to high-altitude training sites, scientists and manufactures have developed artificial high-altitude environments, which simulate the hypoxic conditions of moderate altitude (2000-3000 meters). Endurance athletes from many sports have recently started using nitrogen environments, or hypoxic rooms and tents as part of their altitude training programmes. The results of controlled studies on these modalities of high-altitude training, their practical approach, and ethics are summarised.

Physiological aspects of altitude training and the use of altitude simulators

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Ranković Goran

2005-01-01

Full Text Available Altitude training in various forms is widely practiced by athletes and coaches in an attempt to improve sea level endurance. Training at high altitude may improve performance at sea level through altitude acclimatization, which improves oxygen transport and/or utilization, or through hypoxia, which intensifies the training stimulus. This basic physiological aspect allows three training modalities: live high and train high (classic high-altitude training, live low and train high (training through hypoxia, and live high and train low (the new trend. In an effort to reduce the financial and logistical challenges of traveling to high-altitude training sites, scientists and manufactures have developed artificial high-altitude environments, which simulate the hypoxic conditions of moderate altitude (2000-3000 meters. Endurance athletes from many sports have recently started using nitrogen environments, or hypoxic rooms and tents as part of their altitude training programmes. The results of controlled studies on these modalities of high-altitude training, their practical approach, and ethics are summarized.

Regulation of mRNA translation influences hypoxia tolerance

International Nuclear Information System (INIS)

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

2003-01-01

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

Modest hypoxia significantly reduces triglyceride content and lipid droplet size in 3T3-L1 adipocytes

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Hashimoto, Takeshi, E-mail: thashimo@fc.ritsumei.ac.jp [Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan); Yokokawa, Takumi; Endo, Yuriko [Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan); Iwanaka, Nobumasa [Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan); Higashida, Kazuhiko [Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan); Faculty of Sport Science, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama 359-1192 (Japan); Taguchi, Sadayoshi [Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan)

2013-10-11

Highlights: •Long-term hypoxia decreased the size of LDs and lipid storage in 3T3-L1 adipocytes. •Long-term hypoxia increased basal lipolysis in 3T3-L1 adipocytes. •Hypoxia decreased lipid-associated proteins in 3T3-L1 adipocytes. •Hypoxia decreased basal glucose uptake and lipogenic proteins in 3T3-L1 adipocytes. •Hypoxia-mediated lipogenesis may be an attractive therapeutic target against obesity. -- Abstract: Background: A previous study has demonstrated that endurance training under hypoxia results in a greater reduction in body fat mass compared to exercise under normoxia. However, the cellular and molecular mechanisms that underlie this hypoxia-mediated reduction in fat mass remain uncertain. Here, we examine the effects of modest hypoxia on adipocyte function. Methods: Differentiated 3T3-L1 adipocytes were incubated at 5% O{sub 2} for 1 week (long-term hypoxia, HL) or one day (short-term hypoxia, HS) and compared with a normoxia control (NC). Results: HL, but not HS, resulted in a significant reduction in lipid droplet size and triglyceride content (by 50%) compared to NC (p < 0.01). As estimated by glycerol release, isoproterenol-induced lipolysis was significantly lowered by hypoxia, whereas the release of free fatty acids under the basal condition was prominently enhanced with HL compared to NC or HS (p < 0.01). Lipolysis-associated proteins, such as perilipin 1 and hormone-sensitive lipase, were unchanged, whereas adipose triglyceride lipase and its activator protein CGI-58 were decreased with HL in comparison to NC. Interestingly, such lipogenic proteins as fatty acid synthase, lipin-1, and peroxisome proliferator-activated receptor gamma were decreased. Furthermore, the uptake of glucose, the major precursor of 3-glycerol phosphate for triglyceride synthesis, was significantly reduced in HL compared to NC or HS (p < 0.01). Conclusion: We conclude that hypoxia has a direct impact on reducing the triglyceride content and lipid droplet size via

Modest hypoxia significantly reduces triglyceride content and lipid droplet size in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Hashimoto, Takeshi; Yokokawa, Takumi; Endo, Yuriko; Iwanaka, Nobumasa; Higashida, Kazuhiko; Taguchi, Sadayoshi

2013-01-01

Highlights: •Long-term hypoxia decreased the size of LDs and lipid storage in 3T3-L1 adipocytes. •Long-term hypoxia increased basal lipolysis in 3T3-L1 adipocytes. •Hypoxia decreased lipid-associated proteins in 3T3-L1 adipocytes. •Hypoxia decreased basal glucose uptake and lipogenic proteins in 3T3-L1 adipocytes. •Hypoxia-mediated lipogenesis may be an attractive therapeutic target against obesity. -- Abstract: Background: A previous study has demonstrated that endurance training under hypoxia results in a greater reduction in body fat mass compared to exercise under normoxia. However, the cellular and molecular mechanisms that underlie this hypoxia-mediated reduction in fat mass remain uncertain. Here, we examine the effects of modest hypoxia on adipocyte function. Methods: Differentiated 3T3-L1 adipocytes were incubated at 5% O 2 for 1 week (long-term hypoxia, HL) or one day (short-term hypoxia, HS) and compared with a normoxia control (NC). Results: HL, but not HS, resulted in a significant reduction in lipid droplet size and triglyceride content (by 50%) compared to NC (p < 0.01). As estimated by glycerol release, isoproterenol-induced lipolysis was significantly lowered by hypoxia, whereas the release of free fatty acids under the basal condition was prominently enhanced with HL compared to NC or HS (p < 0.01). Lipolysis-associated proteins, such as perilipin 1 and hormone-sensitive lipase, were unchanged, whereas adipose triglyceride lipase and its activator protein CGI-58 were decreased with HL in comparison to NC. Interestingly, such lipogenic proteins as fatty acid synthase, lipin-1, and peroxisome proliferator-activated receptor gamma were decreased. Furthermore, the uptake of glucose, the major precursor of 3-glycerol phosphate for triglyceride synthesis, was significantly reduced in HL compared to NC or HS (p < 0.01). Conclusion: We conclude that hypoxia has a direct impact on reducing the triglyceride content and lipid droplet size via

Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor

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Dirksen Uta

2010-07-01

Full Text Available Abstract Background Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor. Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. Methods HIF-1α and HIF-2α immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. Results 17/56 Ewing's tumours were HIF-1α-positive, 15 HIF-2α-positive and 10 positive for HIF-1α and HIF-2α. Expression of HIF-1α and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1α and HIF-2α in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2α in Ewing's. Downstream transcription was HIF-1α-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by ≥ 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Conclusions Co-localisation of HIF-1α and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas.

Exercise and Training at Altitudes: Physiological Effects and Protocols

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Olga Cecilia Vargas Pinilla

2014-01-01

Full Text Available An increase in altitude leads to a proportional fall in the barometric pressure, and a decrease in atmospheric oxygen pressure, producing hypobaric hypoxia that affects, in different degrees, all body organs, systems and functions. The chronically reduced partial pressure of oxygen causes that individuals adapt and adjust to physiological stress. These adaptations are modulated by many factors, including the degree of hypoxia related to altitude, time of exposure, exercise intensity and individual conditions. It has been established that exposure to high altitude is an environmental stressor that elicits a response that contributes to many adjustments and adaptations that influence exercise capacity and endurance performance. These adaptations include in crease in hemoglobin concentration, ventilation, capillary density and tissue myoglobin concentration. However, a negative effect in strength and power is related to a decrease in muscle fiber size and body mass due to the decrease in the training intensity. Many researches aim at establishing how training or living at high altitudes affects performance in athletes. Training methods, such as living in high altitudes training low, and training high-living in low altitudes have been used to research the changes in the physical condition in athletes and how the physiological adaptations to hypoxia can enhanceperformance at sea level. This review analyzes the literature related to altitude training focused on how physiological adaptations to hypoxic environments influence performance, and which protocols are most frequently used to train in high altitudes.

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

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Wen Bixiu; Burgman, Paul; Zanzonico, Pat; O' Donoghue, Joseph; Li, Gloria C.; Ling, C. Clifton [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York (United States); Cai Shangde; Finn, Ron [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States); Blasberg, Ronald; Gelovani, Juri [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States)

2004-11-01

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

Influence of acute normobaric hypoxia on physiological variables and lactate turn point determination in trained men.

Science.gov (United States)

Ofner, Michael; Wonisch, Manfred; Frei, Mario; Tschakert, Gerhard; Domej, Wolfgang; Kröpfl, Julia M; Hofmann, Peter

2014-12-01

The goal of this study is to evaluate the response of physiological variables to acute normobaric hypoxia compared to normoxia and its influence on the lactate turn point determination according to the three-phase model of energy supply (Phase I: metabolically balanced at muscular level; Phase II: metabolically balanced at systemic level; Phase III: not metabolically balanced) during maximal incremental exercise. Ten physically active (VO2max 3.9 [0.49] l·min(-1)), healthy men (mean age [SD]: 25.3 [4.6] yrs.), participated in the study. All participants performed two maximal cycle ergometric exercise tests under normoxic as well as hypoxic conditions (FiO2 = 14%). Blood lactate concentration, heart rate, gas exchange data, and power output at maximum and the first and the second lactate turn point (LTP1, LTP2), the heart rate turn point (HRTP) and the first and the second ventilatory turn point (VETP1, VETP2) were determined. Since in normobaric hypoxia absolute power output (P) was reduced at all reference points (max: 314 / 274 W; LTP2: 218 / 184 W; LTP1: 110 / 96 W), as well as VO2max (max: 3.90 / 3.23 l·min(-1); LTP2: 2.90 / 2.43 l·min(-1); LTP1: 1.66 / 1.52 l·min(-1)), percentages of Pmax at LTP1, LTP2, HRTP and VETP1, VETP2 were almost identical for hypoxic as well as normoxic conditions. Heart rate was significantly reduced at Pmax in hypoxia (max: 190 / 185 bpm), but no significant differences were found at submaximal control points. Blood lactate concentration was not different at maximum, and all reference points in both conditions. Respiratory exchange ratio (RER) (max: 1.28 / 1.08; LTP2: 1.13 / 0.98) and ventilatory equivalents for O2 (max: 43.4 / 34.0; LTP2: 32.1 / 25.4) and CO2 (max: 34.1 / 31.6; LTP2: 29.1 / 26.1) were significantly higher at some reference points in hypoxia. Significant correlations were found between LTP1 and VETP1 (r = 0.778; p better the performance of the athletes the higher is the effect of hypoxiaThe HRTP and LTP2 are

Protein S-glutathionylation induced by hypoxia increases hypoxia-inducible factor-1α in human colon cancer cells.

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Jeon, Daun; Park, Heon Joo; Kim, Hong Seok

2018-01-01

Hypoxia is a common characteristic of many types of solid tumors. Intratumoral hypoxia selects for tumor cells that survive in a low oxygen environment, undergo epithelial-mesenchymal transition, are more motile and invasive, and show gene expression changes driven by hypoxia-inducible factor-1α (HIF-1α) activation. Therefore, targeting HIF-1α is an attractive strategy for disrupting multiple pathways crucial for tumor growth. In the present study, we demonstrated that hypoxia increases the S-glutathionylation of HIF-1α and its protein levels in colon cancer cells. This effect is significantly prevented by decreasing oxidized glutathione as well as glutathione depletion, indicating that S-glutathionylation and the formation of protein-glutathione mixed disulfides is related to HIF-1α protein levels. Moreover, colon cancer cells expressing glutaredoxin 1 are resistant to inducing HIF-1α and expressing hypoxia-responsive genes under hypoxic conditions. Therefore, S-glutathionylation of HIF-1α induced by tumor hypoxia may be a novel therapeutic target for the development of new drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Training small producers in Good Manufacturing Practices for the development of goat milk cheese

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Adriana Noemí RAMÓN

Full Text Available Abstract Training in Good Manufacturing Practices enhances quality during food processing. This paper evaluates GMP training aimed at improving the chemical, sensory and microbiological quality of goat milk cheese. We worked with 26 families that produce cheese as their main source of income. Semi-structured interviews and observation were conducted to select relevant topics. The manufacturing processes were compared and samples were analyzed before and after GMP training. We trained 80% of the producers. Before receiving training, they used to make cheese from raw milk in unhygienic conditions and with little equipment. The products obtained had bad sensory characteristics, cracks, eyes on the pasta, a high number of aerobic mesophilic bacteria and total coliforms. After training, the producers pasteurized the milk and standardized processing procedures, resulting in final products that contained higher protein and calcium content, suitable sensory characteristics, and a significant reduction in microorganisms, with total coliforms falling to ≤ 5.103 UFC/g. Therefore, this study shows that the manufacturing process and the chemical, sensory and microbiological parameters of goat milk cheese improved after GMP training.

Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia

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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.

Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications.

Science.gov (United States)

Vaupel, Peter; Mayer, Arnulf

2014-01-01

Hypoxia is a hallmark of tumors leading to (mal-)adaptive processes, development of aggressive phenotypes and treatment resistance. Based on underlying mechanisms and their duration, two main types of hypoxia have been identified, coexisting with complex spatial and temporal heterogeneities. Chronic hypoxia is mainly caused by diffusion limitations due to enlarged diffusion distances and adverse diffusion geometries (e.g., concurrent vs. countercurrent microvessels, Krogh- vs. Hill-type diffusion geometry) and, to a lesser extent, by hypoxemia (e.g., in anemic patients, HbCO formation in heavy smokers), and a compromised perfusion or flow stop (e.g., due to disturbed Starling forces or intratumor solid stress). Acute hypoxia mainly results from transient disruptions in perfusion (e.g., vascular occlusion by cell aggregates), fluctuating red blood cell fluxes or short-term contractions of the interstitial matrix. In each of these hypoxia subtypes oxygen supply is critically reduced, but perfusion-dependent nutrient supply, waste removal, delivery of anticancer or diagnostic agents, and repair competence can be impaired or may not be affected. This detailed differentiation of tumor hypoxia may impact on our understanding of tumor biology and may aid in the development of novel treatment strategies, tumor detection by imaging and tumor targeting, and is thus of great clinical relevance.

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

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

2015-05-01

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

Altitude training induced alterations in erythrocyte rheological properties: a controlled comparison study in rats.

Science.gov (United States)

Bor-Kucukatay, Melek; Colak, Ridvan; Erken, Gülten; Kilic-Toprak, Emine; Kucukatay, Vural

2014-01-01

Altitude training is frequently used by athletes to improve sea-level performance. However, the objective benefits of altitude training are controversial. This study aimed to investigate the possible alterations in hemorheological parameters in response to altitude training. Sprague Dawley rats, were divided into 6 groups: live low-train low (LLTL), live high-train high (LHTH), live high-train low (LHTL) and their controls live high and low (LHALC), live high (LHC), live low (LLC). LHC and LHTH groups were exposed to hypoxia (15% O2, altitudes of 3000 m), 4 weeks. LHALC and LHTL were exposed to 12 hours hypoxia/normoxia per day, 4 weeks. Hypoxia was maintained by a hypoxic tent. The training protocol corresponded to 60-70% of maximal exercise capacity. Rats of training groups ran on treadmill for 20-30 min/day, 4 days/week, 4 weeks. Erythrocyte deformability of LHC group was increased compared to LHALC and LLC. Deformability of LHTH group was higher than LHALC and LLTL groups. No statistically significant alteration in erythrocyte aggregation parameters was observed. There were no significant relationships between RBC deformability and exercise performance. The results of this study show that, living (LHC) and training at altitude (LHTH) seems more advantageous in hemorheological point of view.

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.

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

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

2016-12-15

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

Teleosts in hypoxia : Aspects of anaerobic metabolism

NARCIS (Netherlands)

Van den Thillart, G.; van Waarde, Aren

1985-01-01

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

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

Science.gov (United States)

2012-01-01

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

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

Directory of Open Access Journals (Sweden)

Joffrey ePelletier

2012-02-01

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

Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival

Energy Technology Data Exchange (ETDEWEB)

Pelletier, Joffrey; Bellot, Grégory [Institute of Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, University of Nice-Sophia Antipolis, Nice (France); Gounon, Pierre; Lacas-Gervais, Sandra [Centre Commun de Microscopie Appliquée, University of Nice-Sophia Antipolis, Nice (France); Pouysségur, Jacques; Mazure, Nathalie M., E-mail: mazure@unice.fr [Institute of Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, University of Nice-Sophia Antipolis, Nice (France)

2012-02-28

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 pO{sub 2} acts as an “alarm” that prepares the cells to face subsequent nutrient depletion and to survive.

Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival

International Nuclear Information System (INIS)

Pelletier, Joffrey; Bellot, Grégory; Gounon, Pierre; Lacas-Gervais, Sandra; Pouysségur, Jacques; Mazure, Nathalie M.

2012-01-01

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 pO 2 acts as an “alarm” that prepares the cells to face subsequent nutrient depletion and to survive.

Flight physiology training experiences and perspectives: survey of 117 pilots.

Science.gov (United States)

Patrão, Luís; Zorro, Sara; Silva, Jorge; Castelo-Branco, Miguel; Ribeiro, João

2013-06-01

Human factors and awareness of flight physiology play a crucial role in flight safety. Even so, international legislation is vague relative to training requirements in hypoxia and altitude physiology. Based on a previously developed survey, an adapted questionnaire was formulated and released online for Portuguese pilots. Specific questions regarding the need for pilot attention monitoring systems were added to the original survey. There were 117 pilots, 2 of whom were women, who completed the survey. Most of the pilots had a light aviation license and flew in unpressurized cabins at a maximum ceiling of 10,000 ft (3048 m). The majority of the respondents never experienced hypoxic symptoms. In general, most of the individuals agreed with the importance of an introductory hypoxia course without altitude chamber training (ACT) for all pilot populations, and with a pilot monitoring system in order to increase flight safety. Generally, most of the pilots felt that hypoxia education and training for unpressurized aircraft is not extensive enough. However, almost all the respondents were willing to use a flight physiology monitoring system in order to improve flight safety.

Hypoxia: From Placental Development to Fetal Programming.

Science.gov (United States)

Fajersztajn, Lais; Veras, Mariana Matera

2017-10-16

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

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

Directory of Open Access Journals (Sweden)

Barker Bridget M

2012-02-01

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

Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function

Science.gov (United States)

McNamee, Eóin N.; Johnson, Darlynn Korns; Homann, Dirk

2014-01-01

Oxygen is a molecule that is central to cellular respiration and viability, yet there are multiple physiologic and pathological contexts in which cells experience conditions of insufficient oxygen availability, a state known as hypoxia. Given the metabolic challenges of a low oxygen environment, hypoxia elicits a range of adaptive responses at the cellular, tissue, and systemic level to promote continued survival and function. Within this context, T lymphocytes are a highly migratory cell type of the adaptive immune system that frequently encounters a wide range of oxygen tensions in both health and disease. It is now clear that oxygen availability regulates T cell differentiation and function, a response orchestrated in large part by the hypoxia-inducible factor transcription factors. Here, we discuss the physiologic scope of hypoxia and hypoxic signaling, the contribution of these pathways in regulating T cell biology, and current gaps in our understanding. Finally, we discuss how emerging therapies that modulate the hypoxic response may offer new modalities to alter T cell function and the outcome of acute and chronic pathologies. PMID:22961658

Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

Directory of Open Access Journals (Sweden)

Korry J. Hintze

2011-01-01

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

Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor

International Nuclear Information System (INIS)

Knowles, Helen J; Schaefer, Karl-Ludwig; Dirksen, Uta; Athanasou, Nicholas A

2010-01-01

Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. HIF-1α and HIF-2α immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. 17/56 Ewing's tumours were HIF-1α-positive, 15 HIF-2α-positive and 10 positive for HIF-1α and HIF-2α. Expression of HIF-1α and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1α and HIF-2α in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2α in Ewing's. Downstream transcription was HIF-1α-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by ≥ 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Co-localisation of HIF-1α and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas

Modification of bacterial cell survival by postirradiation hypoxia

Energy Technology Data Exchange (ETDEWEB)

Vexler, F B; Eidus, L Kh

1986-01-27

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

[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Bekaert, Lien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neurosurgery, Caen (France); CHU de Caen, Service de Neurochirurgie, Caen (France); Valable, Samuel; Collet, Solene; Bordji, Karim; Petit, Edwige; Bernaudin, Myriam [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Lechapt-Zalcman, Emmanuele [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Pathology, Caen (France); Ponte, Keven [CHU de Caen, Department of Neurosurgery, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); Constans, Jean-Marc [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Caen, Department of Neuroradiology, Caen (France); Levallet, Guenaelle [CHU de Caen, Department of Pathology, Caen (France); Branger, Pierre [CHU de Caen, Department of Neurology, Caen (France); Emery, Evelyne [CHU de Caen, Department of Neurosurgery, Caen (France); Manrique, Alain [CHU de Caen, Department of Nuclear Medicine, Caen (France); Barre, Louisa [Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP group, Caen (France); Guillamo, Jean-Sebastien [CHU de Caen, Department of Neurology, Caen (France); Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen (France); CHU de Nimes, Department of Neurology, Nimes (France)

2017-08-15

Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival. In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens. [18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005). Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance. (orig.)

Guide to good practices for the selection, training, and qualification of shift technical advisors

Energy Technology Data Exchange (ETDEWEB)

1993-02-01

The DOE Guide to Good Practices For The Selection, Training, and Qualification of Shift Technical Advisors can be used by any DOE nuclear facility that has implemented the shift technical advisor position. DOE Order 5480-20, ``Personnel Selection, Qualification, Training, and Staffing Requirements at DOE Reactor and Non-Reactor Nuclear Facilities,`` states that only Category A reactors must use shift technical advisor position. However, many DOE nuclear facilities have implemented the shift technical advisor position to provide independent on-shift technical advice and counsel to the shift operating personnel to help determine cause and mitigation of facility accidents. Those DOE nuclear facilities that have implemented or are going to implement the shift technical advisor position will find this guide useful. This guide addresses areas that may be covered by other training programs. In these cases, it is unnecessary (and undesirable) to duplicate these areas in the STA training program as long as the specific skills and knowledge essential for STAs are addressed. The guide is presented based on the premise that the trainee has not completed any facility-specific training other than general employee training.

Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis

NARCIS (Netherlands)

Sluimer, Judith C.; Gasc, Jean-Marie; van Wanroij, Job L.; Kisters, Natasja; Groeneweg, Mathijs; Sollewijn Gelpke, Maarten D.; Cleutjens, Jack P.; van den Akker, Luc H.; Corvol, Pierre; Wouters, Bradly G.; Daemen, Mat J.; Bijnens, Ann-Pascale J.

2008-01-01

We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis. Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of

The usability of a 15-gene hypoxia classifier as a universal hypoxia profile in various cancer cell types

DEFF Research Database (Denmark)

Sørensen, Brita Singers; Knudsen, Anders Bisgård; Wittrup, Catja Foged

2015-01-01

genes, with BNIP3 not being upregulated at hypoxic conditions in 3 out of 6 colon cancer cell lines, and ALDOA in OE21 and FAM162A and SLC2A1 in SW116 only showing limited hypoxia induction. Furthermore, in the esophagus cell lines, the normoxic and hypoxic expression levels of LOX and BNIP3 were below...... the tissue type dependency of hypoxia induced genes included in a 15-gene hypoxic profile in carcinoma cell lines from prostate, colon, and esophagus cancer, and demonstrated that in vitro, with minor fluctuations, the genes in the hypoxic profile are hypoxia inducible, and the hypoxia profile may......BACKGROUND AND PURPOSE: A 15-gene hypoxia profile has previously demonstrated to have both prognostic and predictive impact for hypoxic modification in squamous cell carcinoma of the head and neck. This gene expression profile may also have a prognostic value in other histological cancer types...

Cycling hypoxia: A key feature of the tumor microenvironment.

Science.gov (United States)

Michiels, Carine; Tellier, Céline; Feron, Olivier

2016-08-01

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

In vivo characterization of a reporter gene system for imaging hypoxia-induced gene expression.

Science.gov (United States)

Carlin, Sean; Pugachev, Andrei; Sun, Xiaorong; Burke, Sean; Claus, Filip; O'Donoghue, Joseph; Ling, C Clifton; Humm, John L

2009-10-01

To characterize a tumor model containing a hypoxia-inducible reporter gene and to demonstrate utility by comparison of reporter gene expression to the uptake and distribution of the hypoxia tracer (18)F-fluoromisonidazole ((18)F-FMISO). Three tumors derived from the rat prostate cancer cell line R3327-AT were grown in each of two rats as follows: (1) parental R3327-AT, (2) positive control R3327-AT/PC in which the HSV1-tkeGFP fusion reporter gene was expressed constitutively, (3) R3327-AT/HRE in which the reporter gene was placed under the control of a hypoxia-inducible factor-responsive promoter sequence (HRE). Animals were coadministered a hypoxia-specific marker (pimonidazole) and the reporter gene probe (124)I-2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-iodouracil ((124)I-FIAU) 3 h prior to sacrifice. Statistical analysis of the spatial association between (124)I-FIAU uptake and pimonidazole fluorescent staining intensity was then performed on a pixel-by-pixel basis. Utility of this system was demonstrated by assessment of reporter gene expression versus the exogenous hypoxia probe (18)F-FMISO. Two rats, each bearing a single R3327-AT/HRE tumor, were injected with (124)I-FIAU (3 h before sacrifice) and (18)F-FMISO (2 h before sacrifice). Statistical analysis of the spatial association between (18)F-FMISO and (124)I-FIAU on a pixel-by-pixel basis was performed. Correlation coefficients between (124)I-FIAU uptake and pimonidazole staining intensity were: 0.11 in R3327-AT tumors, -0.66 in R3327-AT/PC and 0.76 in R3327-AT/HRE, confirming that only in the R3327-AT/HRE tumor was HSV1-tkeGFP gene expression associated with hypoxia. Correlation coefficients between (18)F-FMISO and (124)I-FIAU uptakes in R3327-AT/HRE tumors were r=0.56, demonstrating good spatial correspondence between the two tracers. We have confirmed hypoxia-specific expression of the HSV1-tkeGFP fusion gene in the R3327-AT/HRE tumor model and demonstrated the utility of this model for the

In vivo characterization of a reporter gene system for imaging hypoxia-induced gene expression

International Nuclear Information System (INIS)

Carlin, Sean; Pugachev, Andrei; Sun Xiaorong; Burke, Sean; Claus, Filip; O'Donoghue, Joseph; Ling, C. Clifton; Humm, John L.

2009-01-01

Purpose: To characterize a tumor model containing a hypoxia-inducible reporter gene and to demonstrate utility by comparison of reporter gene expression to the uptake and distribution of the hypoxia tracer 18 F-fluoromisonidazole ( 18 F-FMISO). Methods: Three tumors derived from the rat prostate cancer cell line R3327-AT were grown in each of two rats as follows: (1) parental R3327-AT, (2) positive control R3327-AT/PC in which the HSV1-tkeGFP fusion reporter gene was expressed constitutively, (3) R3327-AT/HRE in which the reporter gene was placed under the control of a hypoxia-inducible factor-responsive promoter sequence (HRE). Animals were coadministered a hypoxia-specific marker (pimonidazole) and the reporter gene probe 124 I-2'-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-iodouracil ( 124 I-FIAU) 3 h prior to sacrifice. Statistical analysis of the spatial association between 124 I-FIAU uptake and pimonidazole fluorescent staining intensity was then performed on a pixel-by-pixel basis. Utility of this system was demonstrated by assessment of reporter gene expression versus the exogenous hypoxia probe 18 F-FMISO. Two rats, each bearing a single R3327-AT/HRE tumor, were injected with 124 I-FIAU (3 h before sacrifice) and 18 F-FMISO (2 h before sacrifice). Statistical analysis of the spatial association between 18 F-FMISO and 124 I-FIAU on a pixel-by-pixel basis was performed. Results: Correlation coefficients between 124 I-FIAU uptake and pimonidazole staining intensity were: 0.11 in R3327-AT tumors, -0.66 in R3327-AT/PC and 0.76 in R3327-AT/HRE, confirming that only in the R3327-AT/HRE tumor was HSV1-tkeGFP gene expression associated with hypoxia. Correlation coefficients between 18 F-FMISO and 124 I-FIAU uptakes in R3327-AT/HRE tumors were r=0.56, demonstrating good spatial correspondence between the two tracers. Conclusions: We have confirmed hypoxia-specific expression of the HSV1-tkeGFP fusion gene in the R3327-AT/HRE tumor model and demonstrated the utility of

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

Science.gov (United States)

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

1999-04-01

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

Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Induced Transcription

Science.gov (United States)

Chandel, N. S.; Maltepe, E.; Goldwasser, E.; Mathieu, C. E.; Simon, M. C.; Schumacker, P. T.

1998-09-01

Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ 0 cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) ρ 0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ 0 cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.

Cellular prion protein (PrPc and hypoxia: true to each other in good times and in bad, in sickness and in health

Directory of Open Access Journals (Sweden)

Sanja Ramljak

2016-12-01

Full Text Available The cellular prion protein (PrPc and hypoxia appear to be tightly intertwined. Beneficial effects of PrPc on neuronal survival under hypoxic conditions such as focal cerebral ischemia are strongly supported. Conversely, increasing evidence indicates detrimental effects of increased PrPc expression on cancer progression, another condition accompanied by low oxygen tensions. A switch between anaerobic and aerobic metabolism characterizes both conditions. A cellular process that might unite both is glycolysis. Putative role of PrPc in stimulation of glycolysis in times of need is indeed thought provoking. A significance of astrocytic PrPc expression for neuronal survival under hypoxic conditions and possible association of PrPc with the astrocyte-neuron lactate shuttle (ANLS is considered. We posit PrPc-induced lactate production via transactivation of lactate dehydrogenase A by hypoxia inducible factor 1α as an important factor for survival of both neurons and tumor cells in hypoxic microenvironment. Concomitantly, we discuss a cross-talk between Wnt/ß-catenin and PI-3K/Akt signaling pathways in executing PrPc-induced activation of glycolysis. Finally, we would like to emphasize that we see a great potential in joining expertise from both fields, neuroscience and cancer research in revealing the mechanisms underlying hypoxia-related pathologies. PrPc may prove focal point for future research.

The expanding universe of hypoxia.

Science.gov (United States)

Zhang, Huafeng; Semenza, Gregg L

2008-07-01

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

Suppression of the expression of hypoxia-inducible factor-1α by RNA interference alleviates hypoxia-induced pulmonary hypertension in adult rats.

Science.gov (United States)

Li, Ying; Shi, Bo; Huang, Liping; Wang, Xin; Yu, Xiaona; Guo, Baosheng; Ren, Weidong

2016-12-01

Hypoxia-inducible factor-1α (HIF-1α) has been implicated in the pathogenesis of hypoxic pulmonary hypertension (PH). However, the potential clinical value of HIF-1α as a therapeutic target in the treatment of PH has not yet been evaluated. In this study, an animal model of hypoxia-induced PH was established by exposing adult rats to 10% O2 for 3 weeks, and the effects of the lentivirus-mediated delivery of HIF-1α short hairpin RNA (shRNA) by intratracheal instillation prior to exposure to hypoxia on the manifestations of hypoxia-induced PH were assessed. The successful delivery of HIF-1α shRNA into the pulmonary arteries effectively suppressed the hypoxia-induced upregulation of HIF-1α, accompanied by the prominent attenuation the symptoms associated with hypoxia-induced PH, including the elevation of pulmonary arterial pressure, hypertrophy and hyperplasia of pulmonary artery smooth muscle cells (PASMCs), as well as the muscularization of pulmonary arterioles. In addition, the knockdown of HIF-1α in cultured rat primary PASMCs significantly inhibited the hypoxia-induced acceleration of the cell cycle and the proliferation of the PASMCs, suggesting that HIF-1α may be a direct mediator of PASMC hyperplasia in hypoxia-induced PH. In conclusion, this study demonstrates the potent suppressive effects of HIF-1α shRNA on hypoxia-induced PH and PASMC hyperplasia, providing evidence for the potential application of HIF-1α shRNA in the treatment of hypoxic PH.

Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG

DEFF Research Database (Denmark)

Linge, Annett; Löck, Steffen; Gudziol, Volker

2016-01-01

PURPOSE: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Expression...... of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint...... was locoregional tumor control. RESULTS: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA...

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

Directory of Open Access Journals (Sweden)

Peter Vaupel

2014-03-01

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

Vagal activity and oxygen saturation response to hypoxia: Effects of aerobic fitness and rating of hypoxia tolerance

Directory of Open Access Journals (Sweden)

Tomáš Macoun

2017-10-01

Full Text Available Background: A reduction in the inspired oxygen fraction (FiO2 induces a decline in arterial oxygen saturation (SpO2 and changes of heart rate variability (HRV. It has been shown that SpO2 and HRV responses to similar levels of acute normobaric hypoxia are inter-individual variable. Variable response may be influenced by normoxia reached maximal oxygen uptake (VO2max value. Objective: The primary aim was to assess HRV and the SpO2 response to hypoxia, and examine the association with normoxic VO2max. Methods: Supine HRV and SpO2 were monitored during normobaric hypoxia (FiO2 = 9.6% for 10 minutes in 28 subjects, aged 23.7 ± 1.7 years. HRV was evaluated by using both spectral and time domain HRV analysis. Low frequency (LF, 0.05-0.15 Hz and high frequency (HF, 0.15-0.50 Hz power together with square root of the mean of the squares of the successive differences (rMSSD were calculated and transformed by natural logarithm (Ln. Based on the SpO2 in hypoxia, subjects were divided into Resistant (RG, SpO2 ≥ 70.9%, n = 14 and Sensitive (SG, SpO2 < 70.9%, n = 14 groups. Perceived hypoxia tolerance was self-scored on a 4-level scale. Results: VO2max was higher in SG (62.4 ± 7.2 ml ⋅ kg-1 ⋅ min-1 compared with RG (55.5 ± 7.1 ml ⋅ kg-1 ⋅ min-1, p = .017, d = 0.97. A significant relationship (r = -.45, p = .017 between hypoxic-normoxic difference in SpO2 and normoxic VO2max level was found. Vagal activity (Ln rMSSD was significantly decreased (SG: p < .001, d = 2.64; RG: p < .001, d = 1.22, while sympathetic activity (Ln LF/HF was relatively increased (p < .001, d = -1.40 in only the SG during hypoxia. Conclusions: Results show that subjects with a higher aerobic capacity exhibited a greater decline in SpO2, accompanied by greater autonomic cardiac disturbances during hypoxia. The SpO2 reduction was associated with perceived hypoxia comfort/discomfort. The hypoxia

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

Science.gov (United States)

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

2016-01-01

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

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

Science.gov (United States)

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

2016-02-01

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

Understanding and exploiting the genomic response to hypoxia

International Nuclear Information System (INIS)

Giaccia, A.J.

2003-01-01

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

Physiological aspects of altitude training and the use of altitude simulators

OpenAIRE

Ranković Goran; Radovanović Dragan

2005-01-01

Altitude training in various forms is widely practiced by athletes and coaches in an attempt to improve sea level endurance. Training at high altitude may improve performance at sea level through altitude acclimatization, which improves oxygen transport and/or utilization, or through hypoxia, which intensifies the training stimulus. This basic physiological aspect allows three training modalities: live high and train high (classic high-altitude training), live low and train high (training thr...

Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF).

Science.gov (United States)

Xiao, Lin; Kovac, Suzana; Chang, Mike; Shulkes, Arthur; Baldwin, Graham S; Patel, Oneel

2012-07-01

Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.

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

International Nuclear Information System (INIS)

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

2014-01-01

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

Recombinant adeno-associated virus-delivered hypoxia-inducible stanniocalcin-1 expression effectively inhibits hypoxia-induced cell apoptosis in cardiomyocytes.

Science.gov (United States)

Shi, Xin; Wang, Jianzhong; Qin, Yan

2014-12-01

Ischemia/hypoxia-induced oxidative stress is detrimental for the survival of cardiomyocytes and cardiac function. Stanniocalcin-1 (STC-1), a glycoprotein, has been found to play an inhibitory role in the production of reactive oxygen species (ROS). Here, we speculated that the overexpression of STC-1 might alleviate oxidative damage in cardiomyocytes under conditions of hypoxia. To control the expression of STC-1 in hypoxia, we constructed a recombinant adeno-associated virus (AAV) carrying the hypoxia-responsive element (HRE) to mediate hypoxia induction. Cardiomyocytes were infected with AAV-HRE-STC-1 and cultured in normoxic or hypoxic conditions, and STC-1 overexpression was only detected in hypoxic cultured cardiomyocytes by using quantitative real-time polymerase chain reaction and Western blot analysis. Using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, AAV-HRE-STC-1 infection was shown to significantly enhance cell survival under hypoxia. Hypoxia-induced cell apoptosis was inhibited by AAV-HRE-STC-1 infection by using the Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide apoptosis assay. Moreover, the proapoptotic protein Caspase-3 and anti-apoptotic protein Bcl-2, which were dysregulated by hypoxia, were reversed by AAV-HRE-STC-1 infection. AAV-HRE-STC-1-mediated STC-1 overexpression markedly inhibited ROS production in cardiomyocytes cultured under hypoxic conditions. AAV-HRE-STC-1 infection significantly upregulated uncoupled protein 3 (UCP3), whereas silencing of UCP3 blocked the inhibitory effect of AAV-HRE-STC-1 on ROS production. In contrast, AAV-HRE-STC-1 infection had no effect on UCP2, and knockdown of UCP2 did not block the inhibitory effect of AAV-HRE-STC-1 on ROS production in the cardiomyocytes cultured under hypoxic conditions. Taken together, STC1 activates antioxidant pathway in cardiomyocytes through the induction of UCP3, implying that AAV-HRE-STC-1 has potential in the treatment of ischemic

Redox signaling during hypoxia in mammalian cells

Directory of Open Access Journals (Sweden)

Kimberly A. Smith

2017-10-01

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

Intermittent hypoxia increases insulin resistance in genetically obese mice.

Science.gov (United States)

Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

2003-10-01

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P intermittent hypoxia is dependent on the disruption of leptin pathways.

Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis.

Science.gov (United States)

Lee, Dae-Hee; Lee, Yong J

2008-10-01

Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 microM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1alpha accumulation were observed under hypoxic conditions. Treatment with 100 microM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1alpha accumulation during hypoxia. These results suggest that suppression of HIF-1alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis. (c) 2008 Wiley-Liss, Inc.

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

Continuous Positive Airway Pressure Prevents Hypoxia in Dental Patient with Obstructive Sleep Apnea Syndrome under Intravenous Sedation.

Science.gov (United States)

Kasatkin, Anton A; Reshetnikov, Aleksei P; Urakov, Aleksandr L; Baimurzin, Dmitrii Y

2017-01-01

Use of sedation in patients with obstructive sleep apnea (OSA) in dentistry is limited. Hypoxia may develop during medication sleep in dental patients with OSA because of repetitive partial or complete obstruction of the upper airway. In this regard, anesthesiologists prefer not to give any sedative to surgical patients with OSA or support the use of general anesthesia due to good airway control. We report a case where we could successfully sedate a dental patient with OSA using intraoperative continuous positive airway pressure (CPAP) without hypoxia. Use of sedation and intraoperative CPAP in patients with OSA may be considered only if the effectiveness at home CPAP therapy is proven.

Hypoxia-inducible factor signalling mechanisms in the central nervous system.

Science.gov (United States)

Corcoran, A; O'Connor, J J

2013-08-01

In the CNS, neurones are highly sensitive to the availability of oxygen. In conditions where oxygen availability is decreased, neuronal function can be altered, leading to injury and cell death. Hypoxia has been implicated in a number of central nervous system pathologies including stroke, head trauma and neurodegenerative diseases. Cellular responses to oxygen deprivation are complex and result in activation of short- and long-term mechanisms to conserve energy and protect cells. Failure of synaptic transmission can be observed within minutes following this hypoxia. The acute effects of hypoxia on synaptic transmission are primarily mediated by altering ion fluxes across membranes, pre-synaptic effects of adenosine and other actions at glutamatergic receptors. A more long-term feature of the response of neurones to hypoxia is the activation of transcription factors such as hypoxia-inducible factor. The activation of hypoxia-inducible factor is governed by a family of dioxygenases called hypoxia-inducible factor prolyl 4 hydroxylases (PHDs). Under hypoxic conditions, PHD activity is inhibited, thereby allowing hypoxia-inducible factor to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Inhibition of PHD activity stabilizes hypoxia-inducible factor and other proteins thus acting as a neuroprotective agent. This review will focus on the response of neuronal cells to hypoxia-inducible factor and its targets, including the prolyl hydroxylases. We also present evidence for acute effects of PHD inhibition on synaptic transmission and plasticity in the hippocampus. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

The impact of hypoxia on oncolytic virotherapy

Directory of Open Access Journals (Sweden)

Guo ZS

2011-11-01

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

Inflammation and hypoxia in the kidney: friends or foes?

Science.gov (United States)

Haase, Volker H

2015-08-01

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

DOE handbook: Guide to good practices for the selection, training, and qualification of shift supervisors

International Nuclear Information System (INIS)

1999-04-01

This Department of Energy (DOE) handbook is approved for use by all DOE Components and their contractors. The Handbook incorporates editorial changes to DOE-STD-1061-93, ''Guide to Good Practices for the Selection, Training, and Qualification of shift Supervisors,'' and supersedes DOE-STD-1061-93. Technical content of this Handbook has not changed from the original technical standard. Changes are primarily editorial improvements, redesignation of the standard to a Handbook, and format changes to conform with current Technical Standards Program procedures. This guide, used in conjunction with a facility-specific job analysis, provides a framework for the selection, training, qualification, and professional development of reactor facility and non-reactor nuclear facility shift supervisors. Training and qualification programs based on this guide should provide assurance that shift supervisors perform their jobs safely and competently

DOE handbook: Guide to good practices for the selection, training, and qualification of shift supervisors

Energy Technology Data Exchange (ETDEWEB)

NONE

1999-04-01

This Department of Energy (DOE) handbook is approved for use by all DOE Components and their contractors. The Handbook incorporates editorial changes to DOE-STD-1061-93, ``Guide to Good Practices for the Selection, Training, and Qualification of shift Supervisors,`` and supersedes DOE-STD-1061-93. Technical content of this Handbook has not changed from the original technical standard. Changes are primarily editorial improvements, redesignation of the standard to a Handbook, and format changes to conform with current Technical Standards Program procedures. This guide, used in conjunction with a facility-specific job analysis, provides a framework for the selection, training, qualification, and professional development of reactor facility and non-reactor nuclear facility shift supervisors. Training and qualification programs based on this guide should provide assurance that shift supervisors perform their jobs safely and competently.

Physiological determinants of human acute hypoxia tolerance.

Science.gov (United States)

2013-11-01

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

Integrative Analysis of DCE-MRI and Gene Expression Profiles in Construction of a Gene Classifier for Assessment of Hypoxia-Related Risk of Chemoradiotherapy Failure in Cervical Cancer

DEFF Research Database (Denmark)

Fjeldbo, Christina S; Julin, Cathinka H; Lando, Malin

2016-01-01

platforms. The prognostic value was independent of existing clinical markers, regardless of clinical endpoints. CONCLUSIONS: A robust DCE-MRI-associated gene classifier has been constructed that may be used to achieve an early indication of patients' risk of hypoxia-related chemoradiotherapy failure.......PURPOSE: A 31-gene expression signature reflected in dynamic contrast enhanced (DCE)-MR images and correlated with hypoxia-related aggressiveness in cervical cancer was identified in previous work. We here aimed to construct a dichotomous classifier with key signature genes and a predefined...... as an indicator of hypoxia. RESULTS: Classifier candidates were constructed by integrative analysis of ABrix and gene expression profiles in the training cohort and evaluated by a leave-one-out cross-validation approach. On the basis of their ability to separate patients correctly according to hypoxia status, a 6...

Hypoxia is increasing in the coastal zone of the Baltic Sea.

Science.gov (United States)

Conley, Daniel J; Carstensen, Jacob; Aigars, Juris; Axe, Philip; Bonsdorff, Erik; Eremina, Tatjana; Haahti, Britt-Marie; Humborg, Christoph; Jonsson, Per; Kotta, Jonne; Lännegren, Christer; Larsson, Ulf; Maximov, Alexey; Medina, Miguel Rodriguez; Lysiak-Pastuszak, Elzbieta; Remeikaité-Nikiené, Nijolé; Walve, Jakob; Wilhelms, Sunhild; Zillén, Lovisa

2011-08-15

Hypoxia is a well-described phenomenon in the offshore waters of the Baltic Sea with both the spatial extent and intensity of hypoxia known to have increased due to anthropogenic eutrophication, however, an unknown amount of hypoxia is present in the coastal zone. Here we report on the widespread unprecedented occurrence of hypoxia across the coastal zone of the Baltic Sea. We have identified 115 sites that have experienced hypoxia during the period 1955-2009 increasing the global total to ca. 500 sites, with the Baltic Sea coastal zone containing over 20% of all known sites worldwide. Most sites experienced episodic hypoxia, which is a precursor to development of seasonal hypoxia. The Baltic Sea coastal zone displays an alarming trend with hypoxia steadily increasing with time since the 1950s effecting nutrient biogeochemical processes, ecosystem services, and coastal habitat.

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

Science.gov (United States)

Wang, Bin; Wang, Xiaoqin

2015-08-01

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

Hypoxic training increases maximal oxygen consumption in Thoroughbred horses well-trained in normoxia.

Science.gov (United States)

Ohmura, Hajime; Mukai, Kazutaka; Takahashi, Yuji; Takahashi, Toshiyuki; Jones, James H

2017-01-01

Hypoxic training is effective for improving athletic performance in humans. It increases maximal oxygen consumption (V̇O 2 max) more than normoxic training in untrained horses. However, the effects of hypoxic training on well-trained horses are unclear. We measured the effects of hypoxic training on V̇O 2 max of 5 well-trained horses in which V̇O 2 max had not increased over 3 consecutive weeks of supramaximal treadmill training in normoxia which was performed twice a week. The horses trained with hypoxia (15% inspired O 2 ) twice a week. Cardiorespiratory valuables were analyzed with analysis of variance between before and after 3 weeks of hypoxic training. Mass-specific V̇O 2 max increased after 3 weeks of hypoxic training (178 ± 10 vs. 194 ± 12.3 ml O 2 (STPD)/(kg × min), Phorses, at least for the durations of time evaluated in this study. Training while breathing hypoxic gas may have the potential to enhance normoxic performance of Thoroughbred horses.

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

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Hiroshi Harada

2005-07-01

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

The role of mRNA translation in the adaptation to hypoxia

International Nuclear Information System (INIS)

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

2003-01-01

Hypoxia commonly occurs in human tumours and is associated with a poor prognosis. We and others have shown that global mRNA translation is rapidly inhibited during hypoxia. However, some mRNAs, such as those coding for HIF-1 α and VEGF, remain efficiently translated. We therefore hypothesize that the inhibition of mRNA translation serves to promote hypoxia tolerance in two ways: i) through conservation of energy and ii) through differential gene expression involved in hypoxia adaptation. We are investigating the mechanisms responsible for the down regulation of protein synthesis during hypoxia, and how specific mRNAs maintain their ability to be translated under such conditions. Our goal is to understand the significance of these regulatory mechanisms for hypoxia tolerance in vitro and tumor growth in vivo. We have previously shown that one mechanism responsible for inhibiting protein synthesis during hypoxia is the activation of PERK, which inhibits the essential translation factor eIF2 α . Here we show that PERK-/- MEFs are not able to inhibit protein synthesis efficiently during hypoxia and are significantly less tolerant to hypoxia than wt cells. We also show that other mechanisms are important for sustained low protein synthesis during chronic hypoxia. We demonstrate that the eIF4F complex is disrupted during prolonged hypoxia, and that this is mediated by 4E-BP1 and 4E-T. eIF4F is essential for translation which is dependent upon the 5'mRNA cap-structure. These studies therefore indicate a switch from the inhibition of all translation through eIF2 α during acute hypoxia, to the inhibition of only cap-dependent translation during chronic hypoxia. This model predicts the differential induction of genes that can be translated cap-independently during chronic hypoxia, which is consistent with the observed differential translation of HIF-1 α and VEGF. The functional significance of the disruption of the eIF4F complex during hypoxia is currently being addressed

Hypoxia tolerance in coral-reef triggerfishes (Balistidae)

Science.gov (United States)

Wong, Corrie C.; Drazen, Jeffrey C.; Callan, Chatham K.; Korsmeyer, Keith E.

2018-03-01

Despite high rates of photosynthetic oxygen production during the day, the warm waters of coral reefs are susceptible to hypoxia at night due to elevated respiration rates at higher temperatures that also reduce the solubility of oxygen. Hypoxia may be a challenge for coral-reef fish that hide in the reef to avoid predators at night. Triggerfishes (Balistidae) are found in a variety of reef habitats, but they also are known to find refuge in reef crevices and holes at night, which may expose them to hypoxic conditions. The critical oxygen tension ( P crit) was determined as the point below which oxygen uptake could not be maintained to support standard metabolic rate (SMR) for five species of triggerfish. The triggerfishes exhibited similar levels of hypoxia tolerance as other coral-reef and coastal marine fishes that encounter low oxygen levels in their environment. Two species, Rhinecanthus rectangulus and R. aculeatus, had the lowest P crit ( 3.0 kPa O2), comparable to the most hypoxia-tolerant obligate coral-dwelling gobies, while Odonus niger and Sufflamen bursa were moderately tolerant to hypoxia ( P crit 4.5 kPa), and Xanthichthys auromarginatus was intermediate ( P crit 3.7 kPa). These differences in P crit were not due to differences in oxygen demand, as all the species had a similar SMR once mass differences were taken into account. The results suggest that triggerfish species are adapted for different levels of hypoxia exposure during nocturnal sheltering within the reef.

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

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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.

Kinetic modeling in PET imaging of hypoxia

DEFF Research Database (Denmark)

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

2014-01-01

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

Modulation of radioprotective effects of respiratory hypoxia by changing the duration of hypoxia before irradiation and by combining hypoxia and administration of hemopoiesis-stimulating agents

International Nuclear Information System (INIS)

Vacek, A.; Hofer, M.

2001-01-01

Aim: Analysis of radioprotective effect of respiratory hypoxia on hemopoietic tissue and enhancement of this effect by hemopoietic activation. Material and methods: In mice breathing hypoxic gas mixture during total body gamma irradiation the recovery of pluripotent and committed granulocyte-macrophage progenitor cells and animal lethality were determined. Results: In mice forced to breathe 10% O 2 and 8% O 2 during irradiation, the oxygen tension in the spleen decreased to 40% and 20%, respectively, of control values. Hypoxia mitigated the lethal effect of gamma-rays and improved the recovery of hemopoiesis in compartments of pluripotent and committed progenitor cells. Enhancement of the proliferative activity in hemopoietic tissue by a cytokine (rmGM-CSF) or an immunomodulator (dextran sulfate) increased the effect of hypoxic radioprotection, while elimination of proliferative cells by hydroxyurea decreased the radioprotective effect. Adaptation of experimental animals to hypoxic conditions was found to reduce the radioprotective effect without influencing tissue partial oxygen pressure lowered by hypoxic conditions. Conclusion: The data presented confirm the radioprotective effect of 10% and 8% O 2 respiratory hypoxia on hemopoiesis. These findings may represent a way out for further experimental and clinical research aimed at considering differential protection of various tissues by hypoxia. (orig.) [de

Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

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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.

Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma

International Nuclear Information System (INIS)

Zhang, Lin; Feng, Xiaobin; Dong, Jiahong; Qian, Cheng; Huang, Gang; Li, Xiaowu; Zhang, Yujun; Jiang, Yan; Shen, Junjie; Liu, Jia; Wang, Qingliang; Zhu, Jin

2013-01-01

High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT). The expression of EMT markers was analyzed by immunohistochemistry. Effect of hypoxia on induction of EMT and ability of cell migration and invasion were performed. Luciferase reporter system was used for evaluation of Snail regulation by hypoxia-inducible factor -1α (HIF-1α). We found that overexpression of HIF-1α was observed in HCC liver tissues and was related to poor prognosis of HCC patients. HIF-1α expression profile was correlated with the expression levels of SNAI1, E-cadherin, N-cadherin and Vimentin. Hypoxia was able to induce EMT and enhance ability of invasion and migration in HCC cells. The same phenomena were also observed in CoCl2-treated cells. The shRNA-mediated HIF-1α suppression abrogated CoCl2-induced EMT and reduced ability of migration and invasion in HCC cells. Luciferase assay showed that HIF-1α transcriptional regulated the expression of SNAI1 based on two hypoxia response elements (HREs) in SNAI1 promoter. We demonstrated that hypoxia-stabilized HIF1α promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment

Gene expression promoted by the SV40 DNA targeting sequence and the hypoxia-responsive element under normoxia and hypoxia

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C.B. Sacramento

2010-08-01

Full Text Available The main objective of the present study was to find suitable DNA-targeting sequences (DTS for the construction of plasmid vectors to be used to treat ischemic diseases. The well-known Simian virus 40 nuclear DTS (SV40-DTS and hypoxia-responsive element (HRE sequences were used to construct plasmid vectors to express the human vascular endothelial growth factor gene (hVEGF. The rate of plasmid nuclear transport and consequent gene expression under normoxia (20% O2 and hypoxia (less than 5% O2 were determined. Plasmids containing the SV40-DTS or HRE sequences were constructed and used to transfect the A293T cell line (a human embryonic kidney cell line in vitro and mouse skeletal muscle cells in vivo. Plasmid transport to the nucleus was monitored by real-time PCR, and the expression level of the hVEGF gene was measured by ELISA. The in vitro nuclear transport efficiency of the SV40-DTS plasmid was about 50% lower under hypoxia, while the HRE plasmid was about 50% higher under hypoxia. Quantitation of reporter gene expression in vitro and in vivo, under hypoxia and normoxia, confirmed that the SV40-DTS plasmid functioned better under normoxia, while the HRE plasmid was superior under hypoxia. These results indicate that the efficiency of gene expression by plasmids containing DNA binding sequences is affected by the concentration of oxygen in the medium.

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

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Qin Li

2009-12-01

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

Acute physical exercise under hypoxia improves sleep, mood and reaction time.

Science.gov (United States)

de Aquino-Lemos, Valdir; Santos, Ronaldo Vagner T; Antunes, Hanna Karen Moreira; Lira, Fabio S; Luz Bittar, Irene G; Caris, Aline V; Tufik, Sergio; de Mello, Marco Tulio

2016-02-01

This study aimed to assess the effect of two sessions of acute physical exercise at 50% VO2peak performed under hypoxia (equivalent to an altitude of 4500 m for 28 h) on sleep, mood and reaction time. Forty healthy men were randomized into 4 groups: Normoxia (NG) (n = 10); Hypoxia (HG) (n = 10); Exercise under Normoxia (ENG) (n = 10); and Exercise under Hypoxia (EHG) (n = 10). All mood and reaction time assessments were performed 40 min after awakening. Sleep was reassessed on the first day at 14 h after the initiation of hypoxia; mood and reaction time were measured 28 h later. Two sessions of acute physical exercise at 50% VO2peak were performed for 60 min on the first and second days after 3 and 27 h, respectively, after starting to hypoxia. Improved sleep efficiency, stage N3 and REM sleep and reduced wake after sleep onset were observed under hypoxia after acute physical exercise. Tension, anger, depressed mood, vigor and reaction time scores improved after exercise under hypoxia. We conclude that hypoxia impairs sleep, reaction time and mood. Acute physical exercise at 50% VO2peak under hypoxia improves sleep efficiency, reversing the aspects that had been adversely affected under hypoxia, possibly contributing to improved mood and reaction time.

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

International Nuclear Information System (INIS)

Vordermark, D.; Brown, J.M.

2003-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

Vordermark, D. [Dept. of Radiation Oncology, Univ. of Wuerzburg (Germany); Dept. of Radiation Oncology, Stanford Univ. School of Medicine, Stanford, CA (United States); Brown, J.M. [Dept. of Radiation Oncology, Stanford Univ. School of Medicine, Stanford, CA (United States)

2003-12-01

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

Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

International Nuclear Information System (INIS)

Karakashev, Sergey V; Reginato, Mauricio J

2015-01-01

Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance

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.

Impact of hypoxic versus normoxic training on physical fitness and vasculature in diabetes.

NARCIS (Netherlands)

Schreuder, T.H.A.; Nyakayiru, J.; Houben, J.; Thijssen, D.H.J.; Hopman, M.T.E.

2014-01-01

BACKGROUND: Exercise training improves physical fitness, insulin resistance, and endothelial function in type 2 diabetes. Hypoxia may further optimize these beneficial effects. The aim of this study was to compare the effects of hypoxic versus normoxic exercise training on physical fitness,

Does “Live High-Train Low (and High” Hypoxic Training Alter Running Mechanics In Elite Team-sport Players?

Directory of Open Access Journals (Sweden)

Olivier Girard, Grégoire P. Millet, Jean-Benoit Morin, Franck Brocherie

2017-09-01

Full Text Available This study aimed to investigate if “Live High-Train Low (and High” hypoxic training alters constant-velocity running mechanics. While residing under normobaric hypoxia (≥14 h·d-1; FiO2 14.5-14.2% for 14 days, twenty field hockey players performed, in addition to their usual training in normoxia, six sessions (4 × 5 × 5-s maximal sprints; 25 s passive recovery; 5 min rest under either normobaric hypoxia (FiO2 ~14.5%, n = 9 or normoxia (FiO2 20.9%, n = 11. Before and immediately after the intervention, their running pattern was assessed at 10 and 15 km·h-1 as well as during six 30-s runs at ~20 km·h-1 with 30-s passive recovery on an instrumented motorised treadmill. No clear changes in running kinematics and spring-mass parameters occurred globally either at 10, 15 or ~20 km·h-1, with also no significant time × condition interaction for any parameters (p > 0.14. Independently of the condition, heart rate (all p < 0.05 and ratings of perceived exertion decreased post-intervention (only at 15 km·h-1, p < 0.05. Despite indirect signs for improved psycho-physiological responses, no forthright change in stride mechanical pattern occurred after “Live High-Train Low (and High” hypoxic training.

HRGFish: A database of hypoxia responsive genes in fishes

Science.gov (United States)

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

2017-02-01

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

Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain.

Science.gov (United States)

Wang, Kang; Smith, Zachary M; Buxton, Richard B; Swenson, Erik R; Dubowitz, David J

2015-12-15

Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia. Copyright © 2015 the American Physiological Society.

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

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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.

Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes

Directory of Open Access Journals (Sweden)

Shih-Han Kao

2016-02-01

Full Text Available Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT, metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA demethylation mediated by the Ten-eleven translocation (TET proteins induces major epigenetic changes and controls key steps of cancer development. TET enzymes serve as 5mC (5-methylcytosine-specific dioxygenases and cause DNA demethylation. Hypoxia activates the expression of TET1, which also serves as a co-activator of HIF-1α transcriptional regulation to modulate HIF-1α downstream target genes and promote epithelial-mesenchymal transition. As HIF is a negative prognostic factor for tumor progression, hypoxia-activated prodrugs (HAPs may provide a favorable therapeutic approach to lessen hypoxia-induced malignancy.

Radiation, hypoxia and genetic stimulation: implications for future therapies

International Nuclear Information System (INIS)

Adams, Gerald E.; Hasan, Na'il M.; Joiner, Michael C.

1997-01-01

The cellular stress response, whereby very low doses of cytotoxic agents induce resistance to much higher doses, is an evolutionary defence mechanism and is stimulated following challenges by numerous chemical, biological and physical agents including particularly radiation, drugs, heat and hypoxia. There is much homology in the effects of these agents which are manifest through the up-regulation of various genetic pathways. Low-dose radiation stress influences processes involved in cell-cycle control, signal transduction pathways, radiation sensitivity, changes in cell adhesion and cell growth. There is also homology between radiation and other cellular stress agents, particularly hypoxia. Whereas traditionally, hypoxia was regarded mainly as an agent conferring resistance to radiation, there is now much evidence illustrating the cytokine-like properties of hypoxia as well as radiation. Stress phenomena are likely to be important in risks arising from low doses of radiation. Conversely, exploitation of the stress response in settings appropriate to therapy can be particularly beneficial not only in regard to radiation alone but in combinations of radiation and drugs. Similarly, tissue hypoxia can be exploited in novel ways of enhancing therapeutic efficacy. Bioreductive drugs, which are cytotoxically activated in hypoxic regions of tissue, can be rendered even more effective by hypoxia-induced increased expression of enzyme reductases. Nitric oxide pathways are influenced by hypoxia thereby offering possibilities for novel vascular based therapies. Other approaches are discussed

Hypoxia-inducible factor-1α upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction.

Science.gov (United States)

Huang, Tao; Huang, Weiyi; Zhang, Zhiqiang; Yu, Lei; Xie, Caijun; Zhu, Dongan; Peng, Zizhuang; Chen, Jiehan

2014-10-01

Activated microglia were considered to be the toxic inflammatory mediators that induce neuron degeneration after brain ischemia. Hypoxia can enhance the expression of hypoxia-inducible factor-1α (HIF-1α) in microglia and cause microglial activation. However, intermittent hypoxia has been reported recently to be capable of protecting the body from myocardial ischemia. We established a high-altitude environment as the hypoxic condition in this study. The hypoxic condition displayed a neuroprotective effect after brain ischemia, and mice exposed to this condition presented better neurological performance and smaller infarct size. At the same time, a high level of HIF-1α, low level of isoform of nitric oxide synthase, and a reduction in microglial activation were also seen in ischemic focus of hypoxic mice. However, this neuroprotective effect could be blocked by 2-methoxyestradiol, the HIF-1α inhibitor. Our finding suggested that HIF-1α expression was involved in microglial activation in vitro and was regulated by oxygen supply. The microglia were inactivated by re-exposure to hypoxia, which might be due to overexpression of HIF-1α. These results indicated that hypoxic conditions can be exploited to achieve maximum neuroprotection after brain ischemia. This mechanism possibly lies in microglial inactivation through regulation of the expression of HIF-1α.

Hypoxia-based strategies for regenerative dentistry-Views from the different dental fields.

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Müller, Anna Sonja; Janjić, Klara; Lilaj, Bledar; Edelmayer, Michael; Agis, Hermann

2017-09-01

The understanding of the cell biological processes underlying development and regeneration of oral tissues leads to novel regenerative approaches. Over the past years, knowledge on key roles of the hypoxia-based response has become more profound. Based on these findings, novel regenerative approaches for dentistry are emerging, which target cellular oxygen sensors. These approaches include hypoxia pre-conditioning and pharmacologically simulated hypoxia. The increase in studies on hypoxia and hypoxia-based strategies in regenerative dentistry highlights the growing attention to hypoxia's role in regeneration and its underlying biology, as well as its application in a therapeutic setting. In this narrative review, we present the current knowledge on the role of hypoxia in oral tissues and review the proposed hypoxia-based approaches in different fields of dentistry, including endodontics, orthodontics, periodontics, and oral surgery. Copyright © 2017 Elsevier Ltd. All rights reserved.

Individual hemoglobin mass response to normobaric and hypobaric "live high-train low": A one-year crossover study.

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Hauser, Anna; Troesch, Severin; Saugy, Jonas J; Schmitt, Laurent; Cejuela-Anta, Roberto; Faiss, Raphael; Steiner, Thomas; Robinson, Neil; Millet, Grégoire P; Wehrlin, Jon P

2017-08-01

The purpose of this research was to compare individual hemoglobin mass (Hb mass ) changes following a live high-train low (LHTL) altitude training camp under either normobaric hypoxia (NH) or hypobaric hypoxia (HH) conditions in endurance athletes. In a crossover design with a one-year washout, 15 male triathletes randomly performed two 18-day LHTL training camps in either HH or NH. All athletes slept at 2,250 meters and trained at altitudes training camp. Hb mass increased similarly in HH (916-957 g, 4.5 ± 2.2%, P noise): 0.9% in HH and 1.7% in NH. However, a correlation between intraindividual ΔHb mass changes (%) in HH and in NH ( r = 0.52, P = 0.048) was observed. HH and NH evoked similar mean Hb mass increases following LHTL. Among the mean Hb mass changes, there was a notable variation in individual Hb mass response that tended to be reproducible. NEW & NOTEWORTHY This is the first study to compare individual hemoglobin mass (Hb mass ) response to normobaric and hypobaric live high-train low using a same-subject crossover design. The main findings indicate that hypobaric and normobaric hypoxia evoked a similar mean increase in Hb mass following 18 days of live high-train low. Notable variability and reproducibility in individual Hb mass responses between athletes was observed, indicating the importance of evaluating individual Hb mass response to altitude training. Copyright © 2017 the American Physiological Society.

Response of skeletal muscle mitochondria to hypoxia.

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

2003-01-01

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

Radioprotective effect of exogenic hypoxia in fractionated irradiation

International Nuclear Information System (INIS)

Kazymbetov, P.; Yarmonenko, S.P.; Vajnson, A.A.

1988-01-01

During the experiments with mice it is established, that exogenic hypoxia protective effect (8%O 2 ), evaluated according to survival rate, decreases at the change from single to fractionated irradiation. Dose change factor (DCF) is equal to 1.55 and 1.22-1.31, respectively. Skin protection using exogenic hypoxia at the local fractionated irradiation is expressed more, than at the fractionated one. DCF is equal to 1.56 and 1.28, respectively. Exogenic hypoxia protection effect in the tumor is expressed rather weakly. DCF at single and fractionated irradiation constitutes 1.03 and 1.07-1.13, respectively. Due to skin preferential protection the therapeutic gain factor at irradiation under the exogenic hypoxia conditions constitutes 1.24 and 1.38-1.46, respectively, at single and fractionated irradiation

Hypoxia as a biomarker for radioresistant cancer stem cells.

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Peitzsch, Claudia; Perrin, Rosalind; Hill, Richard P; Dubrovska, Anna; Kurth, Ina

2014-08-01

Tumor initiation, growth and relapse after therapy are thought to be driven by a population of cells with stem cell characteristics, named cancer stem cells (CSC). The regulation of their radiation resistance and their maintenance is poorly understood. CSC are believed to reside preferentially in special microenvironmental niches located within tumor tissues. The features of these niches are of crucial importance for CSC self-renewal, metastatic potential and therapy resistance. One of the characteristics of solid tumors is occurrence of less oxygenated (hypoxic regions), which are believed to serve as so-called hypoxic niches for CSC. The purpose of this review was the critical discussion of the supportive role of hypoxia and hypoxia-related pathways during cancer progression and radiotherapy resistance and the relevance for therapeutic implications in the clinic. It is generally known since decades that hypoxia inside solid tumors impedes chemo- and radiotherapy. However, there is limited evidence to date that targeting hypoxic regions during conventional therapy is effective. Nonetheless improved hypoxia-imaging technologies and image guided individualized hypoxia targeted therapy in conjunction with the development of novel molecular targets may be able to challenge the protective effect on the tumor provided by hypoxia.

Radiation-induced hypoxia may perpetuate late normal tissue injury

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

2001-01-01

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

Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols.

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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. © 2015 Wiley Periodicals, Inc.

The radiation response of cells recovering after chronic hypoxia

International Nuclear Information System (INIS)

Kwok, T.T.; Sutherland, R.M.

1989-01-01

Experiments were performed to study the influence of hypoxic pretreatment on the radiation response of A431 human squamous carcinoma cells. Reaeration for 10 min after chronic hypoxia (greater than 2 h) was found to enhance the radiosensitivity of A431 cells, and the maximal effect was seen for those cells reaerated after 12 h of hypoxia. The radiosensitivity enhancement for reaerated cells after 12 h of hypoxia was maximized by 5 min after the return to aerobic conditions and reached the control level by 12 h of reaeration. This enhanced radiosensitive state was characterized by a reduced shoulder region and increased slope of the radiation dose-response curve for cells in both the exponential and plateau phases of growth. There was a slight increase in the number of G1 and decrease in the number of S and G2 + M cells for both exponential- and plateau-phase cultures following 12 h hypoxic treatment. Although growth inhibition induced by 12 h of hypoxia was seen for cells in the exponential phase, there was no cell number change in the plateau-phase culture after hypoxia. Plating efficiency (PE) of cells in both growth phases was reduced by 30% after hypoxia. Furthermore, in the exponential-phase culture, the extent of reduction in PE after hypoxia was similar among cells in different phases of the cell cycle. Although S-phase cells in exponentially growing cultures were relatively more resistant to radiation than G1 and G2 + M cells, the cell age-response pattern was the same whether the cells had been aerobic or hypoxic before reaeration and irradiation. Furthermore, the enhancement ratio associated with reaeration after 12 h of hypoxia for these three subpopulations of cells was 1.3. Our results indicate that the increase in radiosensitivity due to reaeration after chronic hypoxia is unlikely to be related to the changes of cell cycle stage and growth phase during hypoxic treatment

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size.

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Bourdier, Guillaume; Flore, Patrice; Sanchez, Hervé; Pepin, Jean-Louis; Belaidi, Elise; Arnaud, Claire

2016-01-15

Chronic intermittent hypoxia (IH) is described as the major detrimental factor leading to cardiovascular morbimortality in obstructive sleep apnea (OSA) patients. OSA patients exhibit increased infarct size after a myocardial event, and previous animal studies have shown that chronic IH could be the main mechanism. Endoplasmic reticulum (ER) stress plays a major role in the pathophysiology of cardiovascular disease. High-intensity training (HIT) exerts beneficial effects on the cardiovascular system. Thus, we hypothesized that HIT could prevent IH-induced ER stress and the increase in infarct size. Male Wistar rats were exposed to 21 days of IH (21-5% fraction of inspired O2, 60-s cycle, 8 h/day) or normoxia. After 1 wk of IH alone, rats were submitted daily to both IH and HIT (2 × 24 min, 15-30m/min). Rat hearts were either rapidly frozen to evaluate ER stress by Western blot analysis or submitted to an ischemia-reperfusion protocol ex vivo (30 min of global ischemia/120 min of reperfusion). IH induced cardiac proapoptotic ER stress, characterized by increased expression of glucose-regulated protein kinase 78, phosphorylated protein kinase-like ER kinase, activating transcription factor 4, and C/EBP homologous protein. IH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These IH-associated proapoptotic alterations were associated with a significant increase in infarct size (35.4 ± 3.2% vs. 22.7 ± 1.7% of ventricles in IH + sedenary and normoxia + sedentary groups, respectively, P < 0.05). HIT prevented both the IH-induced proapoptotic ER stress and increased myocardial infarct size (28.8 ± 3.9% and 21.0 ± 5.1% in IH + HIT and normoxia + HIT groups, respectively, P = 0.28). In conclusion, these findings suggest that HIT could represent a preventive strategy to limit IH-induced myocardial ischemia-reperfusion damages in OSA patients. Copyright © 2016 the American Physiological Society.

Zeaxanthin Inhibits Hypoxia-Induced VEGF Secretion by RPE Cells through Decreased Protein Levels of Hypoxia-Inducible Factors-1α

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Richard Rosen

2015-01-01

Full Text Available Hypoxia is the most important stimulus leading to upregulation of VEGF in the retina and this is caused by accumulation of hypoxia-inducible factors-1α (HIF-1α protein. The effects of zeaxanthin, a natural phytochemical, on the VEGF and HIF-1α expression in the primary culture of human retinal pigment epithelial (RPE cells were studied. An in vitro RPE cell hypoxia model was established by placing cells under 1% oxygen pressure or by adding cobalt chloride (CoCl2 to the culture medium. RPE cells and conditioned media were collected from cultures treated with and without zeaxanthin under normoxic and hypoxic conditions. VEGF and HIF-1α protein and RNA levels were measured by ELISA kits and RT-PCR, respectively. Hypoxia caused a significant increase of VEGF expression and accumulation of HIF-1α in RPE cells. Zeaxanthin at 50–150 μM significantly inhibited the expression of VEGF and accumulation of HIF-1α protein caused by hypoxia but did not affect expression of VEGF and HIF-1α under normoxic conditions. This is the first report on the effect of zeaxanthin on VEGF and HIF-1α levels in cultured RPE cells and suggests that zeaxanthin may have potential value in the prevention and treatment of various retinal diseases associated with vascular leakage and neovascularization.

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance.

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Salmone, R J; Van Lunteren, E

1991-08-01

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

The Effect of Natural or Simulated Altitude Training on High-Intensity Intermittent Running Performance in Team-Sport Athletes: A Meta-Analysis.

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Hamlin, Michael J; Lizamore, Catherine A; Hopkins, Will G

2018-02-01

While adaptation to hypoxia at natural or simulated altitude has long been used with endurance athletes, it has only recently gained popularity for team-sport athletes. To analyse the effect of hypoxic interventions on high-intensity intermittent running performance in team-sport athletes. A systematic literature search of five journal databases was performed. Percent change in performance (distance covered) in the Yo-Yo intermittent recovery test (level 1 and level 2 were used without differentiation) in hypoxic (natural or simulated altitude) and control (sea level or normoxic placebo) groups was meta-analyzed with a mixed model. The modifying effects of study characteristics (type and dose of hypoxic exposure, training duration, post-altitude duration) were estimated with fixed effects, random effects allowed for repeated measurement within studies and residual real differences between studies, and the standard-error weighting factors were derived or imputed via standard deviations of change scores. Effects and their uncertainty were assessed with magnitude-based inference, with a smallest important improvement of 4% estimated via between-athlete standard deviations of performance at baseline. Ten studies qualified for inclusion, but two were excluded owing to small sample size and risk of publication bias. Hypoxic interventions occurred over a period of 7-28 days, and the range of total hypoxic exposure (in effective altitude-hours) was 4.5-33 km h in the intermittent-hypoxia studies and 180-710 km h in the live-high studies. There were 11 control and 15 experimental study-estimates in the final meta-analysis. Training effects were moderate and very likely beneficial in the control groups at 1 week (20 ± 14%, percent estimate, ± 90% confidence limits) and 4-week post-intervention (25 ± 23%). The intermittent and live-high hypoxic groups experienced additional likely beneficial gains at 1 week (13 ± 16%; 13 ± 15%) and 4-week post

Hypoxia independent drivers of melanoma angiogenesis

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Svenja eMeierjohann

2015-05-01

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

Effects of natural and human-induced hypoxia on coastal benthos

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Levin, L. A.; Ekau, W.; Gooday, A. J.; Jorissen, F.; Middelburg, J. J.; Naqvi, S. W. A.; Neira, C.; Rabalais, N. N.; Zhang, J.

2009-10-01

Coastal hypoxia (defined here as branchial structures, predominate. Large taxa are more sensitive than small taxa to hypoxia. Crustaceans and echinoderms are typically more sensitive to hypoxia, with lower oxygen thresholds, than annelids, sipunculans, molluscs and cnidarians. Mobile fish and shellfish will migrate away from low-oxygen areas. Within a species, early life stages may be more subject to oxygen stress than older life stages. Hypoxia alters both the structure and function of benthic communities, but effects may differ with regional hypoxia history. Human-caused hypoxia is generally linked to eutrophication, and occurs adjacent to watersheds with large populations or agricultural activities. Many occurrences are seasonal, within estuaries, fjords or enclosed seas of the North Atlantic and the NW Pacific Oceans. Benthic faunal responses, elicited at oxygen levels below 2 ml L-1, typically involve avoidance or mortality of large species and elevated abundances of enrichment opportunists, sometimes prior to population crashes. Areas of low oxygen persist seasonally or continuously beneath upwelling regions, associated with the upper parts of oxygen minimum zones (SE Pacific, W Africa, N Indian Ocean). These have a distribution largely distinct from eutrophic areas and support a resident fauna that is adapted to survive and reproduce at oxygen concentrations <0.5 ml L-1. Under both natural and eutrophication-caused hypoxia there is loss of diversity, through attrition of intolerant species and elevated dominance, as well as reductions in body size. These shifts in species composition and diversity yield altered trophic structure, energy flow pathways, and corresponding ecosystem services such as production, organic matter cycling and organic C burial. Increasingly the influences of nature and humans interact to generate or exacerbate hypoxia. A warmer ocean is more stratified, holds less oxygen, and may experience greater advection of oxygen-poor source

Hypoxia-induced retinopathy model in adult zebrafish

DEFF Research Database (Denmark)

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

2010-01-01

Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available....... 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......-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs....

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

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

2009-02-01

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

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

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

2015-05-01

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

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

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Hyun-Joo Park

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

Cold shock protein YB-1 is involved in hypoxia-dependent gene transcription

International Nuclear Information System (INIS)

Rauen, Thomas; Frye, Bjoern C.; Wang, Jialin; Raffetseder, Ute; Alidousty, Christina; En-Nia, Abdelaziz; Floege, Jürgen; Mertens, Peter R.

2016-01-01

Hypoxia-dependent gene regulation is largely orchestrated by hypoxia-inducible factors (HIFs), which associate with defined nucleotide sequences of hypoxia-responsive elements (HREs). Comparison of the regulatory HRE within the 3′ enhancer of the human erythropoietin (EPO) gene with known binding motifs for cold shock protein Y-box (YB) protein-1 yielded strong similarities within the Y-box element and 3′ adjacent sequences. DNA binding assays confirmed YB-1 binding to both, single- and double-stranded HRE templates. Under hypoxia, we observed nuclear shuttling of YB-1 and co-immunoprecipitation assays demonstrated that YB-1 and HIF-1α physically interact with each other. Cellular YB-1 depletion using siRNA significantly induced hypoxia-dependent EPO production at both, promoter and mRNA level. Vice versa, overexpressed YB-1 significantly reduced EPO-HRE-dependent gene transcription, whereas this effect was minor under normoxia. HIF-1α overexpression induced hypoxia-dependent gene transcription through the same element and accordingly, co-expression with YB-1 reduced HIF-1α-mediated EPO induction under hypoxic conditions. Taken together, we identified YB-1 as a novel binding factor for HREs that participates in fine-tuning of the hypoxia transcriptome. - Highlights: • Hypoxia drives nuclear translocation of cold shock protein YB-1. • YB-1 physically interacts with hypoxia-inducible factor (HIF)-1α. • YB-1 binds to the hypoxia-responsive element (HRE) within the erythropoietin (EPO) 3′ enhancer. • YB-1 trans-regulates transcription of hypoxia-dependent genes such as EPO and VEGF.

The individual response to training and competition at altitude.

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Chapman, Robert F

2013-12-01

Performance in athletic activities that include a significant aerobic component at mild or moderate altitudes shows a large individual variation. Physiologically, a large portion of the negative effect of altitude on exercise performance can be traced to limitations of oxygen diffusion, either at the level of the alveoli or the muscle microvasculature. In the lung, the ability to maintain arterial oxyhaemoglobin saturation (SaO₂) appears to be a primary factor, ultimately influencing oxygen delivery to the periphery. SaO₂ in hypoxia can be defended by increasing ventilatory drive; however, during heavy exercise, many athletes demonstrate limitations to expiratory flow and are unable to increase ventilation in hypoxia. Additionally, increasing ventilatory work in hypoxia may actually be negative for performance, if dyspnoea increases or muscle blood flow is reduced secondary to an increased sympathetic outflow (eg, the muscle metaboreflex response). Taken together, some athletes are clearly more negatively affected during exercise in hypoxia than other athletes. With careful screening, it may be possible to develop a protocol for determining which athletes may be the most negatively affected during competition and/or training at altitude.

Communicating Emerging Issues in Ocean Hypoxia (or Suffocating in Your Own Home)

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Whitney, F. A.; Tunnicliffe, V.; Diaz, R. J.

2009-12-01

Some large regions of our interior oceans are losing oxygen both from the impacts of human uses of coastal margins and the impacts that climate change is having on ocean circulation. As oxygen minimum zones expand, impacts are especially noticed along the edges of continents. Ecosystems are being affected in ways that result in habitat compression or forced migrations. Looking into the future, we foresee large scale disruptions to habitat that, in some cases, will dramatically impact fish productivity. As waters become more hypoxic, energy fixed by marine plants will be less available to support higher trophic levels (e.g. fish and marine mammals). Communicating concern about hypoxia has its challenges: the word itself is poorly know to those on land who live in an oxygen-rich world. Thus, crucial factors in effective communication include illustrating: i) how many ocean animals live “on the edge”, ii) how ocean organisms respond to hypoxia iii) the long-term effects on ocean ecosystems and iv) causes and mitigation. For media that respond to visual stimulation, good graphics, evocative analogies and focussed examples are important.

Hypoxia Induces Epithelial-Mesenchymal Transition in Follicular Thyroid Cancer: Involvement of Regulation of Twist by Hypoxia Inducible Factor-1α.

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Yang, Yeon Ju; Na, Hwi Jung; Suh, Michelle J; Ban, Myung Jin; Byeon, Hyung Kwon; Kim, Won Shik; Kim, Jae Wook; Choi, Eun Chang; Kwon, Hyeong Ju; Chang, Jae Won; Koh, Yoon Woo

2015-11-01

Although follicular thyroid cancer (FTC) has a relatively fair prognosis, distant metastasis sometimes results in poor prognosis and survival. There is little understanding of the mechanisms contributing to the aggressiveness potential of thyroid cancer. We showed that hypoxia inducible factor-1α (HIF-1α) induced aggressiveness in FTC cells and identified the underlying mechanism of the HIF-1α-induced invasive characteristics. Cells were cultured under controlled hypoxic environments (1% O₂) or normoxic conditions. The effect of hypoxia on HIF-1α, and epithelial-to-mesenchymal transition (EMT) related markers were evaluated by quantitative real-time PCR, Western blot analysis and immunocytochemistry. Invasion and wound healing assay were conducted to identify functional character of EMT. The involvement of HIF-1α and Twist in EMT were studied using gene overexpression or silencing. After orthotopic nude mouse model was established using the cells transfected with lentiviral shHIF-1α, tissue analysis was done. Hypoxia induces HIF-1α expression and EMT, including typical morphologic changes, cadherin shift, and increased vimentin expression. We showed that overexpression of HIF-1α via transfection resulted in the aforementioned changes without hypoxia, and repression of HIF-1α with RNA interference suppressed hypoxia-induced HIF-1α and EMT. Furthermore, we also observed that Twist expression was regulated by HIF-1α. These were confirmed in the orthotopic FTC model. Hypoxia induced HIF-1α, which in turn induced EMT, resulting in the increased capacity for invasion and migration of cells via regulation of the Twist signal pathway in FTC cells. These findings provide insight into a possible therapeutic strategy to prevent invasive and metastatic FTC.

Mechanisms Causing Hypoxia in the Baltic Sea at Different Spatial and Temporal Scales

Science.gov (United States)

Conley, D. J.; Carstensen, J.; Gustafsson, B.; Slomp, C. P.

2016-02-01

A number of synthesis efforts have documented the world-wide increase in hypoxia, which is primarily driven by nutrient inputs with consequent organic matter enrichment. Physical factors including freshwater or saltwater inputs, stratification and temperature also play an important role in causing and sustaining hypoxia. The Baltic Sea provides an interesting case study to examine changes in oxygen dynamics over time because of the diversity of the types of hypoxia that occur, which ranges from episodic to seasonal hypoxia to perennial hypoxia. Hypoxia varies spatially across the basin with differences between open water bottoms and coastal systems. In addition, the extent and intensity of hypoxia has also varied greatly over the history of the basin, e.g. the last 8000 years. We will examine the mechanisms causing hypoxia at different spatial and temporal scales. The hydrodynamical setting is an important governing factor controlling possible time scales of hypoxia, but enhanced nutrient fluxes and global warming amplify oxygen depletion when oxygen supply by physical processes cannot meet oxygen demands from respiration. Our results indicate that climate change is counteracting management efforts to reduce hypoxia. We will address how hypoxia in the Baltic Sea is terminated at different scales. More importantly, we will explore the prospects of getting rid of hypoxia with the nutrient reductions that have been agreed upon by the countries in the Baltic Sea basin and discuss the time scales of improvement in bottom water oxygen conditions.

Cognition Effects of Low-Grade Hypoxia

Science.gov (United States)

2016-07-01

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

Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack

Energy Technology Data Exchange (ETDEWEB)

Scherbakov, Alexander M., E-mail: alex.scherbakov@gmail.com [Laboratory of Clinical Biochemistry, Institute of Clinical Oncology, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation); Stefanova, Lidia B.; Sorokin, Danila V.; Semina, Svetlana E. [Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation); Berstein, Lev M. [Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg 197758 (Russian Federation); Krasil’nikov, Mikhail A. [Laboratory of Molecular Endocrinology, Institute of Carcinogenesis, N.N. Blokhin Cancer Research Centre, Kashirskoye sh. 24, Moscow 115478 (Russian Federation)

2013-12-10

The tolerance of cancer cells to hypoxia depends on the combination of different factors – from increase of glycolysis (Warburg Effect) to activation of intracellular growth/apoptotic pathways. Less is known about the influence of epithelial–mesenchymal transition (EMT) and EMT-associated pathways on the cell sensitivity to hypoxia. The aim of this study was to explore the role of Snail signaling, one of the key EMT pathways, in the mediating of hypoxia response and regulation of cell sensitivity to hypoxia, using as a model in vitro cultured breast cancer cells. Earlier we have shown that estrogen-independent HBL-100 breast cancer cells differ from estrogen-dependent MCF-7 cells with increased expression of Snail1, and demonstrated Snail1 involvement into formation of hormone-resistant phenotype. Because Snail1 belongs to hypoxia-activated proteins, here we studied the influence of Snail1 signaling on the cell tolerance to hypoxia. We found that Snail1-enriched HBL-100 cells were less sensitive to hypoxia-induced growth suppression if compared with MCF-7 line (31% MCF-7 vs. 71% HBL-100 cell viability after 1% O{sub 2} atmosphere for 3 days). Snail1 knock-down enhanced the hypoxia-induced inhibition of cell proliferation giving the direct evidence of Snail1 involvement into cell protection from hypoxia attack. The protective effect of Snail1 was shown to be mediated, at least in a part, via beta-catenin which positively regulated expression of HIF-1-dependent genes. Finally, we found that cell tolerance to hypoxia was accompanied with the failure in the phosphorylation of AMPK – the key energy sensor, and demonstrated an inverse relationship between AMPK and Snail/beta-catenin signaling. Totally, our data show that Snail1 and beta-catenin, besides association with loss of hormone dependence, protect cancer cells from hypoxia and may serve as an important target in the treatment of breast cancer. Moreover, we suggest that the level of these proteins as well

Altitude Training and its Influence on Physical Endurance in Swimmers

Science.gov (United States)

Strzała, Marek; Ostrowski, Andrzej; Szyguła, Zbigniew

2011-01-01

It is possible to plan an altitude training (AT) period in such a way that the enhanced physical endurance obtained as a result of adaptation to hypoxia will appear and can be used to improve performance in competition. Yet finding rationales for usage of AT in highly trained swimmers is problematic. In practice AT, in its various forms, is still controversial, and an objective review of research concentrating on the advantages and disadvantages of AT has been presented in several scientific publications, including in no small part the observations of swimmers. The aim of this article is to review the various methods and present both the advantageous and unfavourable physiological changes that occur in athletes as a result of AT. Moreover, AT results in the sport of swimming have been collected. They include an approach towards primary models of altitude/hypoxic training: live high + train high, live high + train low, live low + train high, as well as subsequent methods: Intermittent Hypoxic Exposure (IHE) and Intermittent Hypoxic Training (IHT). Apnoea training, which is descended from freediving, is also mentioned, and which can be used with, or as a substitute for, the well-known IHE or IHT methods. In conclusion, swimmers who train using hypoxia may be among the best-trained athletes, and that even a slight improvement in physical endurance might result in the shortening of a swimming time in a given competition, and the achievement of a personal best, which is hard to obtain by normal training methods, when the personal results of the swimmer have reached a plateau. PMID:23486564

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

NARCIS (Netherlands)

Leszczynska, K.B.; Foskolou, I.P.; Abraham, A.G.; Anbalagan, S.; Tellier, C.; Haider, S.; Span, P.N.; O'Neill, E.E.; Buffa, F.M.; Hammond, E.M.

2015-01-01

Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent

Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.

Directory of Open Access Journals (Sweden)

Jennifer Adamski

Full Text Available Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1. In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target

Impact of Hypoxia on the Metastatic Potential of Human Prostate Cancer Cells

International Nuclear Information System (INIS)

Dai Yao; Bae, Kyungmi; Siemann, Dietmar W.

2011-01-01

Purpose: Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells. Methods and Materials: Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. 'Wound-healing' and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography. Results: When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia (≥24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia (≤6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1α. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity. Conclusions: The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

Science.gov (United States)

Leszczynska, Katarzyna B.; Foskolou, Iosifina P.; Abraham, Aswin G.; Anbalagan, Selvakumar; Tellier, Céline; Haider, Syed; Span, Paul N.; O’Neill, Eric E.; Buffa, Francesca M.; Hammond, Ester M.

2015-01-01

Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage–induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain–containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors. PMID:25961455

Brain adaptation to hypoxia and hyperoxia in mice

Directory of Open Access Journals (Sweden)

Laura Terraneo

2017-04-01

Conclusion: Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

[Effect of intermittent hypoxia of sleep apnea on embryonic rat cortical neurons in vitro].

Science.gov (United States)

Zhang, Chanjuan; Li, Yanzhong; Wang, Yan

2015-05-01

To investigate the effects of different pattens of intermittent hypoxia on the activity and apoptosis of primary cultured rat embryonic cortical neurons, and to evaluate the role of intermittent hypoxia in the mechanism of obstructive sleep syndrom induced cognitive function loss. The embryonic cerebral cortical neurons were cultured in vitro and were identified by immunofluorescence. Cultured neurons were randomly divided into intermittent hypoxia group, intermittent normal oxygen group, persistent hypoxia group and the control group, and intermittent hypoxia group was divided into five subgroups according to different frequency and time-bound. Neurons were exposed in different modes of hypoxia. MTT colorimetry was used to detect the viability of the neurons, and DAPI colorated measurement was used to calculate the percentages of neuron apoptosis. There were significantly different effects between all subgroups of intermittent hypoxia and the continued hypoxia group on neuronal activity and apoptosis (P Intermittent hypoxia groups with different frequency and time had no difference in neuronal activity and apoptosis (P > 0.05). The effect of intermittent hypoxia was more serious than that of continued hypoxia on neuronal activity and apoptosis; The impact of intermittent hypoxia on neuronal activity and apoptosis may be an important factor in obstructive sleep apnea related cognitive impairment.

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

Science.gov (United States)

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

2015-11-01

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

Vitamin E supplementation inhibits muscle damage and inflammation after moderate exercise in hypoxia.

Science.gov (United States)

Santos, S A; Silva, E T; Caris, A V; Lira, F S; Tufik, S; Dos Santos, R V T

2016-08-01

Exercise under hypoxic conditions represents an additional stress in relation to exercise in normoxia. Hypoxia induces oxidative stress and inflammation as mediated through tumour necrosis factor (TNF)-α release that might be exacerbated through exercise. In addition, vitamin E supplementation might attenuate oxidative stress and inflammation resulting from hypoxia during exercise. The present study aimed to evaluate the effects of vitamin E supplementation (250 mg) on inflammatory parameters and cellular damage after exercise under hypoxia simulating an altitude of 4200 m. Nine volunteers performed three sessions of 60 min of exercise (70% maximal oxygen uptake) interspersed for 1 week under normoxia, hypoxia and hypoxia after vitamin E supplementation 1 h before exercise. Blood was collected before, immediately after and at 1 h after exercise to measure inflammatory parameters and cell damage. Percentage oxygen saturation of haemoglobin decreased after exercise and recovered 1 h later in the hypoxia + vitamin condition (P exercise (P exercise in hypoxia increased interleukin (IL)-6, TNF-α, IL-1ra and IL-10 immediately after exercise (P exercise in hypoxia without supplementation (P exercise reduces cell damage markers after exercise in hypoxia and changes the concentration of cytokines, suggesting a possible protective effect against inflammation induced by hypoxia during exercise. © 2016 The British Dietetic Association Ltd.

Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?

Science.gov (United States)

Harrison, Louis; Blackwell, Kimberly

2004-01-01

Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO(2)] value effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.

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...

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

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

International Nuclear Information System (INIS)

Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

2013-01-01

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

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

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...... tumours in companion animals hold a great research potential for the evaluation and understanding of tumour hypoxia and in the development of hypoxia-targeting therapeutics....

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

OpenAIRE

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

2009-01-01

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

Training-dependent cognitive advantage is suppressed at high altitude.

Science.gov (United States)

Li, Peng; Zhang, Gang; You, Hai-Yan; Zheng, Ran; Gao, Yu-Qi

2012-06-25

Ascent to high altitude is associated with decreases in cognitive function and work performance as a result of hypoxia. Some workers with special jobs typically undergo intensive mental training because they are expected to be agile, stable and error-free in their job performance. The purpose of this study was to determine the risk to cognitive function acquired from training following hypoxic exposure. The results of WHO neurobehavioral core tests battery (WHO-NCTB) and Raven's standard progressive matrices (RSPM) tests of a group of 54 highly trained military operators were compared with those of 51 non-trained ordinary people and were investigated at sea level and on the fifth day after arrival at high altitudes (3900m). Meanwhile, the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin 1β (IL-1β) and vascular endothelial growth factor (VEGF) were examined. The result showed that at sea level, the trained group exhibited significantly better performance on neurobehavioral and RSPM tests. At high altitude, both groups had decreased accuracy in most cognitive tests and took longer to finish them. More importantly, the highly trained subjects showed more substantial declines than the non-trained subjects in visual reaction accuracy, auditory reaction speed, digit symbol scores, ability to report correct dots in a pursuit aiming test and total RSPM scores. This means that the training-dependent cognitive advantages in these areas were suppressed at high altitudes. The above phenomenon maybe associated with decreased BDNF and elevated inflammatory factor during hypoxia, and other mechanisms could not be excluded. Copyright © 2012 Elsevier Inc. All rights reserved.

Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Hong, Beom Ju; Kim, Jong Woo; Jeong, Hoi Bin; Bok, Seo Yeon; Kim, Young Eun; Ahn, G One [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang (Korea, Republic of)

2016-12-15

Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of ‘reoxygenation’ phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because ‘reoxygenation’ is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn’t it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

Kinetic modeling in PET imaging of hypoxia

Science.gov (United States)

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

2014-01-01

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

Does “Live High-Train Low (and High)” Hypoxic Training Alter Running Mechanics In Elite Team-sport Players?

Science.gov (United States)

Girard, Olivier; Millet, Grégoire P.; Morin, Jean-Benoit; Brocherie, Franck

2017-01-01

This study aimed to investigate if “Live High-Train Low (and High)” hypoxic training alters constant-velocity running mechanics. While residing under normobaric hypoxia (≥14 h·d-1; FiO2 14.5-14.2%) for 14 days, twenty field hockey players performed, in addition to their usual training in normoxia, six sessions (4 × 5 × 5-s maximal sprints; 25 s passive recovery; 5 min rest) under either normobaric hypoxia (FiO2 ~14.5%, n = 9) or normoxia (FiO2 20.9%, n = 11). Before and immediately after the intervention, their running pattern was assessed at 10 and 15 km·h-1 as well as during six 30-s runs at ~20 km·h-1 with 30-s passive recovery on an instrumented motorised treadmill. No clear changes in running kinematics and spring-mass parameters occurred globally either at 10, 15 or ~20 km·h-1, with also no significant time × condition interaction for any parameters (p > 0.14). Independently of the condition, heart rate (all p < 0.05) and ratings of perceived exertion decreased post-intervention (only at 15 km·h-1, p < 0.05). Despite indirect signs for improved psycho-physiological responses, no forthright change in stride mechanical pattern occurred after “Live High-Train Low (and High)” hypoxic training. Key points There are indirect signs for improved psycho-physiological responses in responses to “Live High-Train Low (and High)” hypoxic training. This hypoxic training regimen, however, does not modify the running mechanics of elite team-sport players at low and high velocities. Coaches can be confident that this intervention, known for inducing significant metabolic benefits, is appropriate for athletes since their running kinetics and kinematics are not negatively affected by chronic hypoxic exposure. PMID:28912649

Effects of hypoxia on serum hepatic chemistries of Tibet chicken and ...

African Journals Online (AJOL)

Hypoxia is a major factor that affects the subsistence and development of multicellular organisms. Tibet chicken, as a unique native chicken breed in altiplano, shows genetic adaptation to hypoxia comparing with the breeds at the low altitude. In the present study, to explore effects of hypoxia on chicken fetal livers, eggs of ...

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

Hypoxanthine as a measurement of hypoxia.

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Saugstad, O D

1975-04-01

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

Effect of hypoxia on thallium kinetics in cultured chick myocardial cells

International Nuclear Information System (INIS)

Friedman, B.J.; Beihn, R.; Friedman, J.P.

1987-01-01

To assess the effect of hypoxia on cellular thallium-201 ( 201 Tl) uptake and washout independent of coronary flow, we studied thallium kinetics during normoxia and hypoxia in cultured chick ventricular cells. Monolayers of contracting ventricular cells grown on coverslips were placed in a chamber and perfused to asymptote with media containing 201 Tl. Perfusates were equilibrated with 5% CO 2 -95% air or 5% CO 2 -95% nitrogen for normoxia and hypoxia, respectively. Washout thallium kinetics were then observed during perfusion with unlabeled media. Twenty paired experiments were performed, randomly alternating the sequence of normoxia and hypoxia. Pharmacokinetics for thallium were determined by computer using standard formulae. Thallium uptake and washout were best described by assuming that intracellular thallium was contained within a single compartment. Cellular thallium uptake, as well as transfer rate constants for thallium uptake and for thallium washout during normoxia and hypoxia, were compared using paired t-tests. During normoxia and hypoxia, respectively, thallium uptake was 22 +/- 7% and 19 +/- 7% of asymptote (p less than 0.01); the compartmental rate constant for uptake by the cell was 0.16 +/- 0.07 min-1 and 0.15 +/- 0.06 min-1 (N.S.); and the transfer rate constant for washout from the cell was 0.26 +/- 0.06 min-1 and 0.23 +/- 0.05 min-1 (p less than 0.01). We conclude that there was a small (14%) decrease in thallium uptake during hypoxia. The rate of thallium uptake and washout was slightly less during hypoxia, although only the rate of washout was significantly less. These data show that cellular accumulation of thallium and the rate of washout of thallium were minimally decreased by hypoxia independent of blood flow

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

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

2014-01-01

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

Induction of Gastrin Expression in Gastrointestinal Cells by Hypoxia or Cobalt Is Independent of Hypoxia-Inducible Factor (HIF)

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Xiao, Lin; Kovac, Suzana; Chang, Mike; Shulkes, Arthur; Baldwin, Graham S.; Patel, Oneel

2012-01-01

Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporte...

Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

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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. Copyright © 2015 the authors 0270-6474/15/350527-17$15.00/0.

Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite.

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Zhu, X.; Heunks, L.M.A.; Versteeg, E.M.M.; Heijden, E. van der; Ennen, L.; Kuppevelt, A.H.M.S.M. van; Vina, J.; Dekhuijzen, P.N.R.

2005-01-01

Oxidants may play a role in hypoxia-induced respiratory muscle dysfunction. In the present study we hypothesized that hypoxia-induced impairment in diaphragm contractility is associated with elevated peroxynitrite generation. In addition, we hypothesized that strenuous contractility of the diaphragm

COMPARISON OF LIVE HIGH: TRAIN LOW ALTITUDE AND INTERMITTENT HYPOXIC EXPOSURE

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Clare E. Humberstone-Gough

2013-09-01

Full Text Available Live High:Train Low (LHTL altitude training is a popular ergogenic aid amongst athletes. An alternative hypoxia protocol, acute (60-90 min daily Intermittent Hypoxic Exposure (IHE, has shown potential for improving athletic performance. The aim of this study was to compare directly the effects of LHTL and IHE on the running and blood characteristics of elite triathletes. Changes in total haemoglobin mass (Hbmass, maximal oxygen consumption (VO2max, velocity at VO2max (vVO2max, time to exhaustion (TTE, running economy, maximal blood lactate concentration ([La] and 3 mM [La] running speed were compared following 17 days of LHTL (240 h of hypoxia, IHE (10.2 h of hypoxia or Placebo treatment in 24 Australian National Team triathletes (7 female, 17 male. There was a clear 3.2 ± 4.8% (mean ± 90% confidence limits increase in Hbmass following LHTL compared with Placebo, whereas the corresponding change of -1.4 ± 4.5% in IHE was unclear. Following LHTL, running economy was 2.8 ± 4.4% improved compared to IHE and 3mM [La] running speed was 4.4 ± 4.5% improved compared to Placebo. After IHE, there were no beneficial changes in running economy or 3mM [La] running speed compared to Placebo. There were no clear changes in VO2max, vVO2max and TTE following either method of hypoxia. The clear difference in Hbmass response between LHTL and IHE indicated that the dose of hypoxia in IHE was insufficient to induce accelerated erythropoiesis. Improved running economy and 3mM [La] running speed following LHTL suggested that this method of hypoxic exposure may enhance performance at submaximal running speeds. Overall, there was no evidence to support the use of IHE in elite triathletes

The effects of altitude training on the AMPK-related glucose transport pathway in the red skeletal muscle of both lean and obese Zucker rats.

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Chen, Yu-Ching; Lee, Shin-Da; Kuo, Cha-Hua; Ho, Low-Tone

2011-01-01

The skeletal muscle AMP-activated protein kinase (AMPK)-related glucose transport pathway is involved in glucose homeostasis. In this study, we examined whether obese control Zucker rats had abnormal expression of proteins in the LKB1-AMPK-AS160-GLUT4 pathway in red gastrocnemius muscle compared to that in lean (normal) control Zucker rats. We also compared the chronic training effects of exercise, hypoxia, and altitude training on this pathway in lean and obese rats. At sea level, lean and obese rats were divided into 4 groups for 6 weeks training as follows: 1) control; 2) exercise (progressive daily swimming-exercise training with comparable exercise signals between the two groups); 3) hypoxia (8 hours of daily 14% O2 exposure); and 4) exercise plus hypoxia (also called altitude training). Seven animals were used for each group. The obese rats in the control group had higher body weights, elevated fasting insulin and glucose levels, and higher baseline levels of muscle AMPK and AS160 phosphorylation compared with those of lean control rats. For obese Zucker rats in the exercise or hypoxia groups, the muscle AMPK phosphorylation level was significantly decreased compared with that of the control group. For obese Zucker rats in the altitude training group, the levels of AMPK, AS160 phosphorylation, fasting insulin, and fasting glucose were decreased concomitant with an approximate 50% increase in the muscle GLUT4 protein level compared with those of the control group. In lean rats, the altitude training efficiently lowered fasting glucose and insulin levels and increased muscle AMPK and AS160 phosphorylation as well as GLUT4 protein levels. Our results provide evidence that long-term altitude training may be a potentially effective nonpharmacological strategy for treating and preventing insulin resistance based on its effects on the skeletal muscle AMPK-AS160-GLUT4 pathway.

Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.

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Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

2015-08-01

Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Exercise is good for your blood pressure: effects of endurance training and resistance training.

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Fagard, R H

2006-09-01

1. Although several epidemiological studies have not observed significant independent relationships between physical activity or fitness and blood pressure, others have concluded that blood pressure is lower in individuals who are more fit or active. However, longitudinal intervention studies are more appropriate for assessing the effects of physical activity on blood pressure. 2. Previously, we have performed meta-analyses of randomized controlled trials involving dynamic aerobic endurance training or resistance training. Inclusion criteria were: random allocation to intervention and control; physical training as the sole intervention; inclusion of healthy sedentary normotensive and/or hypertensive adults; intervention duration of at least 4 weeks; availability of systolic and/or diastolic blood pressure; and publication in a peer-reviewed journal up to December 2003. 3. The meta-analysis on endurance training involved 72 trials and 105 study groups. After weighting for the number of trained participants, training induced significant net reductions of resting and day time ambulatory blood pressure of 3.0/2.4 mmHg (P hypertensive study groups (-6.9/-4.9) than in the others (-1.9/-1.6; P training has been less well studied. A meta-analysis of nine randomized controlled trials (12 study groups) on mostly dynamic resistance training revealed a weighted net reduction of diastolic blood pressure of 3.5 mmHg (P endurance training decreases blood pressure through a reduction of systemic vascular resistance, in which the sympathetic nervous system and the renin-angiotensin system appear to be involved, and favourably affects concomitant cardiovascular risk factors. In addition, the few available data suggest that resistance training is able to reduce blood pressure.

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

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

2015-04-03

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

Susceptibility to hypoxia and breathing control changes after short-term cold exposures

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Lyudmila T. Kovtun

2013-08-01

Full Text Available Background . Hypoxia is the reduction of oxygen availability due to external or internal causes. There is large individual variability of response to hypoxia. Objective . The aim of this study was to define individual and typological features in susceptibility to hypoxia, its interrelation with hypoxic and hypercapnic ventilatory responses (HVR and HCVR, respectively and their changes after cold acclimation. Design . Twenty-four healthy men were tested. HVR and HCVR were measured by the rebreathing method during hypoxic and hypercapnic tests, respectively. These tests were carried out in thermoneutral conditions before and after cold exposures (nude, at 13°C, 2 h daily, for 10 days. Susceptibility to hypoxia (sSaO2 was determined as haemoglobin saturation slope during hypoxic test. Results . It was found that HVR and HCVR significantly increased and susceptibility to hypoxia (sSaO2 tended to decrease after cold acclimation. According to sSaO2 results before cold exposures, the group was divided into 3: Group 1 – with high susceptibility to hypoxia, Group 2 – medium and Group 3 – low susceptibility. Analysis of variances (MANOVA shows the key role of susceptibility to hypoxia and cold exposures and their interrelation. Posterior analysis (Fisher LSD showed significant difference in susceptibility to hypoxia between the groups prior to cold acclimation, while HVR and HCVR did not differ between the groups. After cold acclimation, susceptibility to hypoxia was not significantly different between the groups, while HCVR significantly increased in Groups 1 and 3, HVR significantly increased in Group 3 and HCVR, HVR did not change in Group 2. Conclusions . Short-term cold exposures caused an increase in functional reserves and improved oxygen supply of tissues in Group 1. Cold exposure hypoxia has caused energy loss in Group 3. Group 2 showed the most appropriate energy conservation reaction mode to cold exposures. No relation was found between

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.

Elevation of hypoxia resistance with the use of gutimine

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Vinogradov, V.M.; Pastushenkov, L.V.; Sumina, E.N.

Experimental data demonstrating the protection from the adverse effects of hypoxia offered by the antioxidant gutimine and its analogs are presented. The experiments included preliminary studies of hypoxia resistance and recovery under simulated altitude, studies of circulatory hypoxia in the brain and in intrauterine fetuses, studies of myocardial ischemia during acute and chronic experiments and studies where cardiac, kidney and limb circulation is cut off. The compound was also found to be effective in cases of hemorrhagic hypotension, complex hypoxia in peritonitis, meningococcal meningitis, and the weakening of uterine muscle contractility during prolonged deliveries, and in cranial-cerebral trauma. Mechanisms of the antihypoxic action of gutimine and its analogs have been found to include the reduction of oxygen utilization, the activation of aerobic and anaerobic metabolism, the acceleration of lactate utilization, the inhibition of lipolysis in fat tissue, and stabilization of cell membranes. Clinical observations also support the experimental data.

The cross-tissue metabolic response of abalone (Haliotis midae) to functional hypoxia.

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Venter, Leonie; Loots, Du Toit; Mienie, Lodewyk J; Jansen van Rensburg, Peet J; Mason, Shayne; Vosloo, Andre; Lindeque, Jeremie Z

2018-03-23

Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone ( Haliotis midae) subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids) for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

The cross-tissue metabolic response of abalone (Haliotis midae to functional hypoxia

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Leonie Venter

2018-03-01

Full Text Available Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone (Haliotis midae subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia. This article has an associated First Person interview with the first author of the paper.

Midcervical neuronal discharge patterns during and following hypoxia

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Sandhu, M. S.; Baekey, D. M.; Maling, N. G.; Sanchez, J. C.; Reier, P. J.

2014-01-01

Anatomical evidence indicates that midcervical interneurons can be synaptically coupled with phrenic motoneurons. Accordingly, we hypothesized that interneurons in the C3–C4 spinal cord can display discharge patterns temporally linked with inspiratory phrenic motor output. Anesthetized adult rats were studied before, during, and after a 4-min bout of moderate hypoxia. Neuronal discharge in C3–C4 lamina I–IX was monitored using a multielectrode array while phrenic nerve activity was extracellularly recorded. For the majority of cells, spike-triggered averaging (STA) of ipsilateral inspiratory phrenic nerve activity based on neuronal discharge provided no evidence of discharge synchrony. However, a distinct STA phrenic peak with a 6.83 ± 1.1 ms lag was present for 5% of neurons, a result that indicates a monosynaptic connection with phrenic motoneurons. The majority (93%) of neurons changed discharge rate during hypoxia, and the diverse responses included both increased and decreased firing. Hypoxia did not change the incidence of STA peaks in the phrenic nerve signal. Following hypoxia, 40% of neurons continued to discharge at rates above prehypoxia values (i.e., short-term potentiation, STP), and cells with initially low discharge rates were more likely to show STP (P phrenic motoneuron pool, and these cells can modulate inspiratory phrenic output. In addition, the C3–C4 propriospinal network shows a robust and complex pattern of activation both during and following an acute bout of hypoxia. PMID:25552641

The effects of exercise under hypoxia on cognitive function.

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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.

Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors.

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Aprelikova, Olga; Chandramouli, Gadisetti V R; Wood, Matthew; Vasselli, James R; Riss, Joseph; Maranchie, Jodi K; Linehan, W Marston; Barrett, J Carl

2004-06-01

Hypoxia and induction of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) is a hallmark of many tumors. Under normal oxygen tension HIF-alpha subunits are rapidly degraded through prolyl hydroxylase dependent interaction with the von Hippel-Lindau (VHL) tumor suppressor protein, a component of E3 ubuiquitin ligase complex. Using microarray analysis of VHL mutated and re-introduced cells, we found that one of the prolyl hydroxylases (PHD3) is coordinately expressed with known HIF target genes, while the other two family members (PHD1 and 2) did not respond to VHL. We further tested the regulation of these genes by HIF-1 and HIF-2 and found that siRNA targeted degradation of HIF-1alpha and HIF-2alpha results in decreased hypoxia-induced PHD3 expression. Ectopic overexpression of HIF-2alpha in two different cell lines provided a much better induction of PHD3 gene than HIF-1alpha. In contrast, we demonstrate that PHD2 is not affected by overexpression or downregulation of HIF-2alpha. However, induction of PHD2 by hypoxia has HIF-1-independent and -dependent components. Short-term hypoxia (4 h) results in induction of PHD2 independent of HIF-1, while PHD2 accumulation by prolonged hypoxia (16 h) was decreased by siRNA-mediated degradation of HIF-1alpha subunit. These data further advance our understanding of the differential role of HIF factors and putative feedback loop in HIF regulation. Copyright 2004 Wiley-Liss, Inc.

Comparing the effect of hypercapnia and hypoxia on the electroencephalogram during wakefulness.

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Wang, David; Yee, Brendon J; Wong, Keith K; Kim, Jong Won; Dijk, Derk-Jan; Duffin, James; Grunstein, Ronald R

2015-01-01

Hypoxia has been postulated as a key mechanism for neurocognitive impairment in sleep-disordered breathing. However, the effect of hypoxia on the electroencephalogram (EEG) is not clear. We examined quantitative EEG recordings from 20 normal volunteers under three 5-min ventilatory control protocols: progressive hypercapnia with iso-hyperoxia (pO2=150mmHg) (Protocol 1), progressive hypercapnia with iso-hypoxia (pO2=50mmHg) (Protocol 2), and progressive hypoxia with a CO2 scrubber in the circuit (Protocol 3). Each protocol started with a 5-min session of breathing room air as baseline. In Protocol 1, compared to its baseline, iso-hyperoxia hypercapnia led to a lower Alpha% and higher Delta/Alpha (D/A) ratio. Similarly, in Protocol 2, the iso-hypoxia hypercapnia induced a higher Delta%, a lower Alpha% and higher D/A ratio. No difference was found in any EEG spectral band including the D/A ratio when Protocols 1 & 2 were compared. In Protocol 3, the Delta%, Alpha% and D/A ratio recorded during hypoxia were not significantly different from baseline. We found that hypercapnia, but not hypoxia, may play a key role in slowing of the EEG in healthy humans. Hypercapnia may be a greater influence than hypoxia on brain neuroelectrical activities. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Identification of Hypoxia-Regulated Proteins Using MALDI-Mass Spectrometry Imaging Combined with Quantitative Proteomics

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Djidja, Marie-Claude; Chang, Joan; Hadjiprocopis, Andreas

2014-01-01

Hypoxia is present in most solid tumors and is clinically correlated with increased metastasis and poor patient survival. While studies have demonstrated the role of hypoxia and hypoxia-regulated proteins in cancer progression, no attempts have been made to identify hypoxia-regulated proteins using...

Fatty Acid Biosynthesis Inhibition Increases Reduction Potential in Neuronal Cells under Hypoxia

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Stephen A Brose

2016-11-01

Full Text Available Recently, we have reported a novel neuronal specific pathway for adaptation to hypoxia through increased fatty acid (FA biosynthesis (FAS followed by esterification into lipids. However, the biological role of this pathway under hypoxia remains to be elucidated. In the presented study, we have tested our hypothesis that activation of FAS maintains reduction potential and reduces lactoacidosis in neuronal cells under hypoxia. To address this hypothesis, we measured the effect of FAS inhibition on NADH2+/NAD+ and NADPH2+/NADP+ ratios, and lactic acid levels in neuronal SH-SY5Y cells exposed to normoxic and hypoxic conditions. FAS inhibitors, TOFA (inhibits Acetyl-CoA carboxylase and cerulenin (inhibits FA synthase, increased NADH2+/NAD+ and NADPH2+/NADP+ ratios under hypoxia. Further, FAS inhibition increased lactic acid under both normoxic and hypoxic conditions, and caused cytotoxicity under hypoxia but not normoxia. These results indicate that FA may serve as hydrogen acceptors under hypoxia, thus supporting oxidation reactions including anaerobic glycolysis. These findings may help to identify a radically different approach to attenuate hypoxia related pathophysiology in the nervous system including stroke.

Fatty Acid Biosynthesis Inhibition Increases Reduction Potential in Neuronal Cells under Hypoxia.

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Brose, Stephen A; Golovko, Svetlana A; Golovko, Mikhail Y

2016-01-01

Recently, we have reported a novel neuronal specific pathway for adaptation to hypoxia through increased fatty acid (FA) biosynthesis followed by esterification into lipids. However, the biological role of this pathway under hypoxia remains to be elucidated. In the presented study, we have tested our hypothesis that activation of FA synthesis maintains reduction potential and reduces lactoacidosis in neuronal cells under hypoxia. To address this hypothesis, we measured the effect of FA synthesis inhibition on [Formula: see text]/NAD + and [Formula: see text]/NADP + ratios, and lactic acid levels in neuronal SH-SY5Y cells exposed to normoxic and hypoxic conditions. FA synthesis inhibitors, TOFA (inhibits Acetyl-CoA carboxylase) and cerulenin (inhibits FA synthase), increased [Formula: see text]/NAD + and [Formula: see text]/NADP + ratios under hypoxia. Further, FA synthesis inhibition increased lactic acid under both normoxic and hypoxic conditions, and caused cytotoxicity under hypoxia but not normoxia. These results indicate that FA may serve as hydrogen acceptors under hypoxia, thus supporting oxidation reactions including anaerobic glycolysis. These findings may help to identify a radically different approach to attenuate hypoxia related pathophysiology in the nervous system including stroke.

Hypoxia-inducible transcription factor-1α promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway

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Luo, FengMing; Liu, XiaoJing; Yan, NaiHong; Li, ShuangQing; Cao, GuiQun; Cheng, QingYing; Xia, QingJie; Wang, HongJing

2006-01-01

Hypoxia-inducible transcription factor-1α (HIF-1α), which plays an important role in controlling the hypoxia-induced glycolysis pathway, is a 'master' gene in the tissue hypoxia response during tumor development. However, its role in the apoptosis of non-small cell lung cancer remains unknown. Here, we have studied the effects of HIF-1α on apoptosis by modulating HIF-1α gene expression in A549 cells through both siRNA knock-down and over-expression. A549 cells were transfected with a HIF-1α siRNA plasmid or a HIF-1α expression vector. Transfected cells were exposed to a normoxic or hypoxic environment in the presence or absence of 25 mM HEPES and 2-deoxyglucose (2-DG) (5 mM). The expression of three key genes of the glycolysis pathway, glucose transporter type 1(GLUT1), phosphoglycerate kinase 1(PGK1), and hexokinase 1(HK1), were measured using real-time RT-PCR. Glycolysis was monitored by measuring changes of pH and lactate concentration in the culture medium. Apoptosis was detected by TUNEL assay and flow cytometry. Knocking down expression of HIF-1α inhibited the glycolysis pathway, increased the pH of the culture medium, and protected the cells from hypoxia-induced apoptosis. In contrast, over-expression of HIF-1α accelerated glycolysis in A549 cells, decreased the pH of the culture medium, and enhanced hypoxia-induced apoptosis. These effects of HIF-1α on glycolysis, pH of the medium, and apoptosis were reversed by treatment with the glycolytic inhibitor, 2-DG. Apoptosis induced by HIF-1α over-expression was partially inhibited by increasing the buffering capacity of the culture medium by adding HEPES. During hypoxia in A549 cells, HIF-1α promotes activity of the glycolysis pathway and decreases the pH of the culture medium, resulting in increased cellular apoptosis

Automatic Quantification of Tumour Hypoxia From Multi-Modal Microscopy Images Using Weakly-Supervised Learning Methods.

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Carneiro, Gustavo; Peng, Tingying; Bayer, Christine; Navab, Nassir

2017-07-01

In recently published clinical trial results, hypoxia-modified therapies have shown to provide more positive outcomes to cancer patients, compared with standard cancer treatments. The development and validation of these hypoxia-modified therapies depend on an effective way of measuring tumor hypoxia, but a standardized measurement is currently unavailable in clinical practice. Different types of manual measurements have been proposed in clinical research, but in this paper we focus on a recently published approach that quantifies the number and proportion of hypoxic regions using high resolution (immuno-)fluorescence (IF) and hematoxylin and eosin (HE) stained images of a histological specimen of a tumor. We introduce new machine learning-based methodologies to automate this measurement, where the main challenge is the fact that the clinical annotations available for training the proposed methodologies consist of the total number of normoxic, chronically hypoxic, and acutely hypoxic regions without any indication of their location in the image. Therefore, this represents a weakly-supervised structured output classification problem, where training is based on a high-order loss function formed by the norm of the difference between the manual and estimated annotations mentioned above. We propose four methodologies to solve this problem: 1) a naive method that uses a majority classifier applied on the nodes of a fixed grid placed over the input images; 2) a baseline method based on a structured output learning formulation that relies on a fixed grid placed over the input images; 3) an extension to this baseline based on a latent structured output learning formulation that uses a graph that is flexible in terms of the amount and positions of nodes; and 4) a pixel-wise labeling based on a fully-convolutional neural network. Using a data set of 89 weakly annotated pairs of IF and HE images from eight tumors, we show that the quantitative results of methods (3) and (4

Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1.

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Pan, Rong; Chen, Chen; Liu, Wen-Lan; Liu, Ke-Jian

2013-07-01

Pathological release of excess zinc ions has been implicated in ischemic brain cell death. However, the underlying mechanisms remain to be elucidated. In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue. The present study tests the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1α during hypoxia, which significantly contributes to cell death during ischemia. Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride. Cell death rate and protein expression of HIF-1 and Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment. Although 3-h hypoxia or 100 μM of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner. Exposure of astrocytes to hypoxia for 3 h remarkably increased the levels of intracellular zinc and HIF-1α protein, which was further augmented by added exogenous zinc. Notably, HIF-1α knockdown blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1α and reduced the cell death rate. Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1α via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury. © 2013 John Wiley & Sons Ltd.

An insert-based enzymatic cell culture system to rapidly and reversibly induce hypoxia: investigations of hypoxia-induced cell damage, protein expression and phosphorylation in neuronal IMR-32 cells

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Ying Huang

2013-11-01

Ischemia-reperfusion injury and tissue hypoxia are of high clinical relevance because they are associated with various pathophysiological conditions such as myocardial infarction and stroke. Nevertheless, the underlying mechanisms causing cell damage are still not fully understood, which is at least partially due to the lack of cell culture systems for the induction of rapid and transient hypoxic conditions. The aim of the study was to establish a model that is suitable for the investigation of cellular and molecular effects associated with transient and long-term hypoxia and to gain insights into hypoxia-mediated mechanisms employing a neuronal culture system. A semipermeable membrane insert system in combination with the hypoxia-inducing enzymes glucose oxidase and catalase was employed to rapidly and reversibly generate hypoxic conditions in the culture medium. Hydrogen peroxide assays, glucose measurements and western blotting were performed to validate the system and to evaluate the effects of the generated hypoxia on neuronal IMR-32 cells. Using the insert-based two-enzyme model, hypoxic conditions were rapidly induced in the culture medium. Glucose concentrations gradually decreased, whereas levels of hydrogen peroxide were not altered. Moreover, a rapid and reversible (onoff generation of hypoxia could be performed by the addition and subsequent removal of the enzyme-containing inserts. Employing neuronal IMR-32 cells, we showed that 3 hours of hypoxia led to morphological signs of cellular damage and significantly increased levels of lactate dehydrogenase (a biochemical marker of cell damage. Hypoxic conditions also increased the amounts of cellular procaspase-3 and catalase as well as phosphorylation of the pro-survival kinase Akt, but not Erk1/2 or STAT5. In summary, we present a novel framework for investigating hypoxia-mediated mechanisms at the cellular level. We claim that the model, the first of its kind, enables researchers to rapidly and

Hypoxic hypoxia as a means of modifying radiosensibility

International Nuclear Information System (INIS)

Neumeister, K.; Niemiec, C.; Bolck, M.; Jahns, J.; Kamprad, F.; Arnold, P.; Johannsen, U.; Koch, F.; Mehlhorn, G.

1977-01-01

Following an overview of the various possibilities of creating hypoxia in mammals, the problem of reducing radioresistance of hypoxic tumor cells is treated. Furthermore, the results of irradiation experiments with mice, rats and pigs breathing hypoxic mixtures of O 2 and N 2 are given and discussed with a view to applying hypoxic hypoxia in the radiotherapy of human tumors. (author)

Culture media from hypoxia conditioned endothelial cells protect human intestinal cells from hypoxia/reoxygenation injury.

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Hummitzsch, Lars; Zitta, Karina; Bein, Berthold; Steinfath, Markus; Albrecht, Martin

2014-03-10

Remote ischemic preconditioning (RIPC) is a phenomenon, whereby short episodes of non-lethal ischemia to an organ or tissue exert protection against ischemia/reperfusion injury in a distant organ. However, there is still an apparent lack of knowledge concerning the RIPC-mediated mechanisms within the target organ and the released factors. Here we established a human cell culture model to investigate cellular and molecular effects of RIPC and to identify factors responsible for RIPC-mediated intestinal protection. Human umbilical vein cells (HUVEC) were exposed to repeated episodes of hypoxia (3 × 15 min) and conditioned culture media (CM) were collected after 24h. Human intestinal cells (CaCo-2) were cultured with or without CM and subjected to 90 min of hypoxia/reoxygenation injury. Reverse transcription-polymerase chain reaction, Western blotting, gelatin zymography, hydrogen peroxide measurements and lactate dehydrogenase (LDH) assays were performed. In HUVEC cultures hypoxic conditioning did not influence the profile of secreted proteins but led to an increased gelatinase activity (Pcultures 90 min of hypoxia/reoxygenation resulted in morphological signs of cell damage, increased LDH levels (Pculture model may help to unravel RIPC-mediated cellular events and to identify molecules released by RIPC. Copyright © 2014 Elsevier Inc. All rights reserved.

Dose prescription and treatment planning based on FMISO-PET hypoxia

International Nuclear Information System (INIS)

Toma-Dasu, Iuliana; Antonovic, Laura; Uhrdin, Johan; Dasu, Alexandru; Nuyts, Sandra; Dirix, Piet; Haustermans, Karin; Brahme, Anders

2012-01-01

Purpose. The study presents the implementation of a novel method for incorporating hypoxia information from PET-CT imaging into treatment planning and estimates the efficiency of various optimization approaches. Its focuses on the feasibility of optimizing treatment plans based on the non-linear conversion of PET hypoxia images into radiosensitivity maps from the uptake properties of the tracers used. Material and methods. PET hypoxia images of seven head-and-neck cancer patients were used to determine optimal dose distributions needed to counteract the radiation resistance associated with tumor hypoxia assuming various scenarios regarding the evolution of the hypoxic compartment during the treatment. A research planning system for advanced studies has been used to optimize IMRT plans based on hypoxia information from patient PET images. These resulting plans were compared in terms of target coverage for the same fulfilled constraints regarding the organs at risk. Results. The results of a planning study indicated the clinical feasibility of the proposed method for treatment planning based on PET hypoxia. Antihypoxic strategies would lead to small improvements in all the patients, but higher effects are expected for the fraction of patients with hypoxic tumors. For these, individualization of the treatment based on hypoxia PET imaging could lead to improved treatment outcome while creating the premises for limiting the irradiation of the surrounding normal tissues. Conclusions. The proposed approach offers the possibility of improved treatment results as it takes into consideration the heterogeneity and the dynamics of the hypoxic regions. It also provides early identification of the clinical cases that might benefit from dose escalation as well as the cases that could benefit from other counter-hypoxic measures

Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses.

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Serebrovskaya, Tatiana V; Xi, Lei

2015-01-01

Intermittent hypoxia (IH) often occurs in early infancy in both preterm and term infants and especially at 36-44 weeks postmenstrual age. These episodes of IH could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of IH on development, behavior, academic achievement, and cognition in children with sleep apnea syndrome. It remains uncertain about the exact causative relationship between the neurocognitive and behavioral morbidities and IH and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate IH conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g., hypercapnia, polycythemia), in order to prevent or reduce its harmful consequences, while maximizing its potential utility as an effective therapeutic tool in pediatric patients.

Hypoxia-ischemia and retinal ganglion cell damage

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Charanjit Kaur

2008-08-01

Full Text Available Charanjit Kaur1, Wallace S Foulds2, Eng-Ang Ling11Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Singapore Eye Research Institute, SingaporeAbstract: Retinal hypoxia is the potentially blinding mechanism underlying a number of sight-threatening disorders including central retinal artery occlusion, ischemic central retinal vein thrombosis, complications of diabetic eye disease and some types of glaucoma. Hypoxia is implicated in loss of retinal ganglion cells (RGCs occurring in such conditions. RGC death occurs by apoptosis or necrosis. Hypoxia-ischemia induces the expression of hypoxia inducible factor-1α and its target genes such as vascular endothelial growth factor (VEGF and nitric oxide synthase (NOS. Increased production of VEGF results in disruption of the blood retinal barrier leading to retinal edema. Enhanced expression of NOS results in increased production of nitric oxide which may be toxic to the cells resulting in their death. Excess glutamate release in hypoxic-ischemic conditions causes excitotoxic damage to the RGCs through activation of ionotropic and metabotropic glutamate receptors. Activation of glutamate receptors is thought to initiate damage in the retina by a cascade of biochemical effects such as neuronal NOS activation and increase in intracellular Ca2+ which has been described as a major contributing factor to RGC loss. Excess production of proinflammatory cytokines also mediates cell damage. Besides the above, free-radicals generated in hypoxic-ischemic conditions result in RGC loss because of an imbalance between antioxidant- and oxidant-generating systems. Although many advances have been made in understanding the mediators and mechanisms of injury, strategies to improve the damage are lacking. Measures to prevent neuronal injury have to be developed.Keywords: retinal hypoxia, retinal ganglion cells, glutamate receptors, neuronal injury, retina

Hypoxia-driven angiogenesis: role of tip cells and extracellular matrix scaffolding.

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Germain, Stéphane; Monnot, Catherine; Muller, Laurent; Eichmann, Anne

2010-05-01

Angiogenesis is a highly coordinated tissue remodeling process leading to blood vessel formation. Hypoxia triggers angiogenesis via induction of expression of growth factors such as vascular endothelial growth factor (VEGF). VEGF instructs endothelial cells to form tip cells, which lead outgrowing capillary sprouts, whereas Notch signaling inhibits sprout formation. Basement membrane deposition and mechanical cues from the extracellular matrix (ECM) induced by hypoxia may participate to coordinated vessel sprouting in conjunction with the VEGF and Notch signaling pathways. Hypoxia regulates ECM composition, deposition, posttranslational modifications and rearrangement. In particular, hypoxia-driven vascular remodeling is dynamically regulated through modulation of ECM-modifying enzyme activities that eventually affect both matricellular proteins and growth factor availability. Better understanding of the complex interplay between endothelial cells and soluble growth factors and mechanical factors from the ECM will certainly have significant implications for understanding the regulation of developmental and pathological angiogenesis driven by hypoxia.

Three hours of intermittent hypoxia increases circulating glucose levels in healthy adults.

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Newhouse, Lauren P; Joyner, Michael J; Curry, Timothy B; Laurenti, Marcello C; Man, Chiara Dalla; Cobelli, Claudio; Vella, Adrian; Limberg, Jacqueline K

2017-01-01

An independent association exists between sleep apnea and diabetes. Animal models suggest exposure to intermittent hypoxia, a consequence of sleep apnea, results in altered glucose metabolism and fasting hyperglycemia. However, it is unknown if acute exposure to intermittent hypoxia increases glucose concentrations in nondiabetic humans. We hypothesized plasma glucose would be increased from baseline following 3 h of intermittent hypoxia in healthy humans independent of any effect on insulin sensitivity. Eight (7M/1F, 21-34 years) healthy subjects completed two study visits randomized to 3 h of intermittent hypoxia or continuous normoxia, followed by an oral glucose tolerance test. Intermittent hypoxia consisted of 25 hypoxic events per hour where oxygen saturation (SpO 2 ) was significantly reduced (Normoxia: 97 ± 1%, Hypoxia: 90 ± 2%, P  0.05). In contrast, circulating glucose concentrations were increased after 3 h of intermittent hypoxia when compared to baseline (5.0 ± 0.2 vs. 5.3 ± 0.2 mmol/L, P = 0.01). There were no detectable changes in insulin sensitivity following intermittent hypoxia when compared to continuous normoxia, as assessed by the oral glucose tolerance test (P > 0.05). Circulating glucose is increased after 3 h of intermittent hypoxia in healthy humans, independent of any lasting changes in insulin sensitivity. These novel findings could explain, in part, the high prevalence of diabetes in patients with sleep apnea and warrant future studies to identify underlying mechanisms. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.

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Laura Asnaghi

Full Text Available The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2 further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.

Effects of natural and human-induced hypoxia on coastal benthos

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L. A. Levin

2009-10-01

Full Text Available Coastal hypoxia (defined here as <1.42 ml L⁻¹; 62.5 μM; 2 mg L⁻¹, approx. 30% oxygen saturation develops seasonally in many estuaries, fjords, and along open coasts as a result of natural upwelling or from anthropogenic eutrophication induced by riverine nutrient inputs. Permanent hypoxia occurs naturally in some isolated seas and marine basins as well as in open slope oxygen minimum zones. Responses of benthos to hypoxia depend on the duration, predictability, and intensity of oxygen depletion and on whether H₂S is formed. Under suboxic conditions, large mats of filamentous sulfide oxidizing bacteria cover the seabed and consume sulfide. They are hypothesized to provide a detoxified microhabitat for eukaryotic benthic communities. Calcareous foraminiferans and nematodes are particularly tolerant of low oxygen concentrations and may attain high densities and dominance, often in association with microbial mats. When oxygen is sufficient to support metazoans, small, soft-bodied invertebrates (typically annelids, often with short generation times and elaborate branchial structures, predominate. Large taxa are more sensitive than small taxa to hypoxia. Crustaceans and echinoderms are typically more sensitive to hypoxia, with lower oxygen thresholds, than annelids, sipunculans, molluscs and cnidarians. Mobile fish and shellfish will migrate away from low-oxygen areas. Within a species, early life stages may be more subject to oxygen stress than older life stages.

Hypoxia alters both the structure and function of benthic communities, but effects may differ with regional hypoxia history. Human-caused hypoxia is generally linked to eutrophication, and occurs adjacent to watersheds with large populations or agricultural activities. Many occurrences are seasonal, within estuaries, fjords or enclosed seas of the North Atlantic and the NW Pacific Oceans. Benthic faunal responses, elicited at oxygen levels below

Training Diaries during Altitude Training Camp in Two Olympic Champions: An Observational Case Study

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Lorenzo Pugliese, Fabio R. Serpiello, Grégoire P. Millet, Antonio La Torre

2014-09-01

Full Text Available Traditionally, Live High-Train High (LHTH interventions were adopted when athletes trained and lived at altitude to try maximising the benefits offered by hypoxic exposure and improving sea level performance. Nevertheless, scientific research has proposed that the possible benefits of hypoxia would be offset by the inability to maintain high training intensity at altitude. However, elite athletes have been rarely recruited as an experimental sample, and training intensity has almost never been monitored during altitude research. This case study is an attempt to provide a practical example of successful LHTH interventions in two Olympic gold medal athletes. Training diaries were collected and total training volumes, volumes at different intensities, and sea level performance recorded before, during and after a 3-week LHTH camp. Both athletes successfully completed the LHTH camp (2090 m maintaining similar absolute training intensity and training volume at high-intensity (> 91% of race pace compared to sea level. After the LHTH intervention both athletes obtained enhancements in performance and they won an Olympic gold medal. In our opinion, LHTH interventions can be used as a simple, yet effective, method to maintain absolute, and improve relative training intensity in elite endurance athletes.

Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

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Nicole Horrée

2007-01-01

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

Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus.

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Bethany L Peterson

Full Text Available Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6 and older (postnatal day 20 age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus.

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Peterson, Bethany L; Larson, John; Buffenstein, Rochelle; Park, Thomas J; Fall, Christopher P

2012-01-01

Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

Effects of hypoxia on human cancer cell line chemosensitivity

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2013-01-01

Background Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, (hypoxia). It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on five different cell lines in conditions of normoxia, hypoxia and anoxia. Methods A panel of 19 commercially available drugs: 5-fluorouracil, acriflavine, bortezomib, cisplatin, digitoxin, digoxin, docetaxel, doxorubicin, etoposide, gemcitabine, irinotecan, melphalan, mitomycin c, rapamycin, sorafenib, thalidomide, tirapazamine, topotecan and vincristine were tested for cytotoxic activity on the cancer cell lines A2780 (ovarian), ACHN (renal), MCF-7 (breast), H69 (SCLC) and U-937 (lymphoma). Parallel aliquots of the cells were grown at different oxygen pressures and after 72 hours of drug exposure viability was measured with the fluorometric microculture cytotoxicity assay (FMCA). Results Sorafenib, irinotecan and docetaxel were in general more effective in an oxygenated environment, while cisplatin, mitomycin c and tirapazamine were more effective in a low oxygen environment. Surprisingly, hypoxia in H69 and MCF-7 cells mostly rendered higher drug sensitivity. In contrast ACHN appeared more sensitive to hypoxia, giving slower proliferating cells, and consequently, was more resistant to most drugs. Conclusions A panel of standard cytotoxic agents was tested against five different human cancer cell lines cultivated at normoxic, hypoxic and anoxic conditions. Results show that impaired chemosensitivity is not universal, in contrast different cell lines behave different and some drugs appear even less effective in normoxia than hypoxia. PMID:23829203

Hypoxia-Related Hormonal Appetite Modulation in Humans during Rest and Exercise: Mini Review

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Tadej Debevec

2017-05-01

Full Text Available Obesity is associated with numerous chronic ailments and represents one of the major health and economic issues in the modernized societies. Accordingly, there is an obvious need for novel treatment approaches. Recently, based on the reports of reduced appetite and subsequent weight loss following high-altitude sojourns, exposure to hypoxia has been proposed as a viable weight-reduction strategy. While altitude-related appetite modulation is complex and not entirely clear, hypoxia-induced alterations in hormonal appetite modulation might be among the key underlying mechanisms. The present paper summarizes the up-to-date research on hypoxia/altitude-induced changes in the gut and adipose tissue derived peptides related to appetite regulation. Orexigenic hormone ghrelin and anorexigenic peptides leptin, glucagon-like peptide-1, peptide YY, and cholecystokinin have to-date been investigated as potential modulators of hypoxia-driven appetite alterations. Current evidence suggests that hypoxia can, especially acutely, lead to decreased appetite, most probably via reduction of acylated ghrelin concentration. Hypoxia-related short and long-term changes in other hormonal markers are more unclear although hypoxia seems to importantly modulate leptin levels, especially following prolonged hypoxic exposures. Limited evidence also suggests that different activity levels during exposures to hypoxia do not additively affect hormonal appetite markers. Although very few studies have been performed in obese/overweight individuals, the available data indicate that hypoxia/altitude exposures do not seem to differentially affect appetite regulation via hormonal pathways in this cohort. Given the lack of experimental data, future well-controlled acute and prolonged studies are warranted to expand our understanding of hypoxia-induced hormonal appetite modulation and its kinetics in health and disease.

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

Science.gov (United States)

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

2016-08-05

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

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation.

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Santacruz, Lucia; Arciniegas, Antonio Jose Luis; Darrabie, Marcus; Mantilla, Jose G; Baron, Rebecca M; Bowles, Dawn E; Mishra, Rajashree; Jacobs, Danny O

2017-08-01

Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Cerebral circulation, metabolism, and blood-brain barrier of rats in hypocapnic hypoxia

International Nuclear Information System (INIS)

Beck, T.; Krieglstein, J.

1987-01-01

The effects of hypoxic hypoxia on physiological variables, cerebral circulation, cerebral metabolism, and blood-brain barrier were investigated in conscious, spontaneously breathing rats by exposing them to an atmosphere containing 7% O 2 . Hypoxia affected a marked hypotension, hypocapnia and alkalosis. Cortical tissue high-energy phosphates and glucose content were not affected by hypoxia, glucose 6-phosphate lactate, and pyruvate levels were significantly increased. Blood-brain barrier permeability, regional brain glucose content and lumped constant were not changed by hypoxia. Local cerebral glucose utilization (LCGU) rose by 40-70% of control values in gray matter and by 80-90% in white matter. Under hypoxia, columns of increased and decreased LCGU and were detectable in cortical gray matter. Color-coded [ 14 C]2-deoxy-D-glucose autoradiograms of rat brain are shown. Local cerebral blood flow (LCBF) increased by 50-90% in gray matter and by up to 180% in white matter. Coupling between LCGU and LCBF in hypoxia remained unchanged. The data suggests a stimulation of glycolysis, increased glucose transport into the cell, and increased hexokinase activity. The physiological response of gray and white matter to hypoxia obviously differs. Uncoupling of the relation between LCGU and LCBF does not occur

Living at high altitude in combination with sea-level sprint training increases hematological parameters but does not improve performance in rats.

Science.gov (United States)

Martinez-Bello, Vladimir Essau; Sanchis-Gomar, Fabian; Nascimento, Ana Lucia; Pallardo, Federico V; Ibañez-Sania, Sandra; Olaso-Gonzalez, Gloria; Calbet, Jose Antonio; Gomez-Cabrera, Mari Carmen; Viña, Jose

2011-06-01

The regimen of aerobic training at sea level with recovery at high altitude has been used by athletes to improve performance. However, little is known about the effects of hypoxia when combined with sprint interval training on performance. The aim of the present study was to determine the effect of a "living high-sprint training low" strategy on hemoglobin, hematocrit and erythropoietin levels in rats. We also wanted to test whether the addition of a hypoxic stress to the program of daily treadmill running at high speeds induces expressional adaptations in skeletal muscle and affects performance. The protein content of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), cytochrome C, pyruvate dehydrogenase kinase (PDK1), heat shock protein 70 (HSP70), manganese superoxide dismutase (MnSOD) and citrate synthase activity were determined in different muscle fiber types in our animals (red and white gastrocnemius muscle). We also determined the maximal aerobic velocity (MAV) before and after the training period. A total of 24 male Wistar rats (3 month old) were randomly divided into four experimental groups: the normoxic control group (n = 6), the normoxic trained group (n = 6), the hypoxic control group (12 h pO(2) 12%/12 h pO(2) 21%) (n = 6) and the hypoxic trained group (12 h pO(2) 12%/12 h pO(2) 21%). Living in normobaric hypoxia condition for 21 days significantly increased hemoglobin, hematocrit and erythropoietin levels in both the rest and the trained groups. The trained animals (normoxia and hypoxia) significantly increased their maximal aerobic velocity. No changes were found in the skeletal muscle in PGC-1α, cytochrome C, PDK1, HSP70, MnSOD protein content and in the citrate synthase activity in any experimental group. Regardless of whether it is combined with sprint interval training or not, after 21 days of living at high altitude we found a significant increase in the hematological values determined in our study. However, contrary to

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

DEFF Research Database (Denmark)

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

2015-01-01

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

Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

African Journals Online (AJOL)

Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

Intrauterine hypoxia: clinical consequences and therapeutic perspectives

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Thompson LP

2015-09-01

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

Nutritional status in chronic obstructive pulmonary disease: role of hypoxia.

Science.gov (United States)

Raguso, Comasia A; Luthy, Christophe

2011-02-01

In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of "growth hormone resistance." Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation. Copyright © 2011 Elsevier Inc. All rights reserved.

Hypoxia inhibits hypertrophic differentiation and endochondral ossification in explanted tibiae.

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Jeroen C H Leijten

Full Text Available Hypertrophic differentiation of growth plate chondrocytes induces angiogenesis which alleviates hypoxia normally present in cartilage. In the current study, we aim to determine whether alleviation of hypoxia is merely a downstream effect of hypertrophic differentiation as previously described or whether alleviation of hypoxia and consequent changes in oxygen tension mediated signaling events also plays an active role in regulating the hypertrophic differentiation process itself.Fetal mouse tibiae (E17.5 explants were cultured up to 21 days under normoxic or hypoxic conditions (21% and 2.5% oxygen respectively. Tibiae were analyzed on growth kinetics, histology, gene expression and protein secretion.The oxygen level had a strong influence on the development of explanted fetal tibiae. Compared to hypoxia, normoxia increased the length of the tibiae, length of the hypertrophic zone, calcification of the cartilage and mRNA levels of hypertrophic differentiation-related genes e.g. MMP9, MMP13, RUNX2, COL10A1 and ALPL. Compared to normoxia, hypoxia increased the size of the cartilaginous epiphysis, length of the resting zone, calcification of the bone and mRNA levels of hyaline cartilage-related genes e.g. ACAN, COL2A1 and SOX9. Additionally, hypoxia enhanced the mRNA and protein expression of the secreted articular cartilage markers GREM1, FRZB and DKK1, which are able to inhibit hypertrophic differentiation.Collectively our data suggests that oxygen levels play an active role in the regulation of hypertrophic differentiation of hyaline chondrocytes. Normoxia stimulates hypertrophic differentiation evidenced by the expression of hypertrophic differentiation related genes. In contrast, hypoxia suppresses hypertrophic differentiation of chondrocytes, which might be at least partially explained by the induction of GREM1, FRZB and DKK1 expression.

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.

Hypoxia upregulates neutrophil degranulation and potential for tissue injury

Science.gov (United States)

Hoenderdos, Kim; Lodge, Katharine M; Hirst, Robert A; Chen, Cheng; Palazzo, Stefano G C; Emerenciana, Annette; Summers, Charlotte; Angyal, Adri; Porter, Linsey; Juss, Jatinder K; O'Callaghan, Christopher; Chilvers, Edwin R

2016-01-01

Background The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. Methods and results Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. Conclusion Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion. PMID:27581620

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

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Lv Y

2015-07-01

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

Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.

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Min Yu

Full Text Available Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined.Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr-/- and abr-/- macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia.Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells.

A genetically encoded biosensor for visualising hypoxia responses in vivo

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Tvisha Misra

2017-02-01

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

The role of hypoxia, p53, and apoptosis in human cervical carcinoma pathogenesis

International Nuclear Information System (INIS)

Kim, Charlotte Y.; Tsai, Mitchell H.; Osmanian, Cynthia; Calkins, Dennise P.; Graeber, Thomas G.; Greenspan, David L.; Kennedy, Andrew S.; Rinker, Lillian H.; Varia, Mahesh A.; DiPaolo, Joseph A.; Peehl, Donna M.; Raleigh, James A.; Giaccia, Amato J.

1997-01-01

Objective: Low oxygen tension in the tumor microenvironment may have an important role during tumor growth, and is of particular prognostic significance in human cervical carcinoma. Because some human papillomavirus (HPV) infections are associated with cervical neoplasia, the relationship between hypoxia and apoptosis in primary cervical epithelial cells containing HPV16 E6 and E7, intact HPV 16 genome, and HPV positive cervical carcinoma cell lines, was examined. In addition, the relationship between hypoxia and apoptosis in spontaneous human cervical carcinomas was determined in situ. Materials and Methods: Primary normal human cervical epithelial cells were infected with retroviral vectors containing HPV16 E6 and E7 or transfected with a plasmid containing the whole HPV 16 genome. Clones were selected in neomycin containing medium. Exponentially growing cells were incubated under aerobic conditions (20% O 2 ), anaerobic conditions (0.02% O 2 ), or irradiated with 6 Gy. Analysis of apoptotic cells was performed by staining with Hoechst dye and propidium iodide and viewing with a fluorescent microscope. To determine the level of expression of the apoptotic modulators p53 and Bax, immunoblots were performed on whole cell extracts from treated cells. A clinical tumor hypoxia study was conducted at the University of North Carolina utilizing pimonidazole, a 2-nitroimidazole compound which binds irreversibly to cellular macromolecules under low oxygen conditions. Nine patients were enrolled with biopsy proven squamous cell carcinoma of the cervix and no prior treatment. Biopsies of the gross tumor were obtained after pimonidazole infusion. Contiguous histological sections were analyzed for hypoxia using a immunohistochemical technique and for apoptosis using TUNEL. Results: In vitro, hypoxia uncoupled p53 from E6 mediated degradation, and stimulated both p53 induction and apoptosis in primary cervical epithelial cells infected with the HPV E6 and E7 genes. In contrast

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

OpenAIRE

Nishimura, Ryo; Okuda, Kiyoshi

2015-01-01

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

The effect of altitude hypoxia on glucose homeostasis in men

DEFF Research Database (Denmark)

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

1997-01-01

1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia...... (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4. In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes...

Andrographolide inhibits hypoxia-induced hypoxia-inducible factor 1α and endothelin 1 expression through the heme oxygenase 1/CO/cGMP/MKP-5 pathways in EA.hy926 cells.

Science.gov (United States)

Lin, Hung-Chih; Su, Shih-Li; Lin, Wan-Chun; Lin, Ai-Hsuan; Yang, Ya-Chen; Lii, Chong-Kuei; Chen, Haw-Wen

2018-03-01

Andrographolide is a potent anti-inflammatory agent found in Andrographis paniculata. Endothelin 1 (ET-1) is an endothelium-derived vasoconstrictor with pro-inflammatory properties secreted in response to hypoxia. Mitogen-activated protein kinase phosphatase 5 (MKP-5) is a dual-specificity phosphatase that dephosphorylates threonine and tyrosine residues of MAPKs. We showed previously that hypoxia-induced HIF-1α expression and ET-1 secretion are dependent on p38 MAPK in EA.hy926 cells. Here, we investigate what role MKP-5 plays in andrographolide's inhibition of hypoxia-induced expression of HIF-1α and ET-1. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl 2 . Andrographolide enhanced HO-1 and MKP-5 expression and cellular cGMP content in addition to inhibiting hypoxia-induced ROS generation. Concomitantly, the HO-1 byproduct CO and the cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) increased MKP-5 expression, and pretreatment with CO and 8-Br-cGMP inhibited hypoxia-induced HIF-1α and ET-1 expression. Transfection of HO-1 siRNA or pretreatment with the HO-1 inhibitor ZnPP-9 or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific inhibitor of soluble guanylate cyclase, reduced andrographolide-induced MKP-5 expression. Moreover, silencing MKP-5 or treatment with the phosphatase inhibitor vanadate abrogated andrographolide's suppressing hypoxia-induced p38 MAPK activation and HIF-1α expression. The inhibition of hypoxia-induced HIF-1α and ET-1 expression by andrographolide is likely associated with HO-1/CO/cGMP/MKP-5 pathways, which is involved in inhibiting hypoxia-induced p38 MAPK activation. © 2017 Wiley Periodicals, Inc.

Optical imaging of tumor hypoxia dynamics

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

2010-11-01

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

Notch signaling mediates hypoxia-induced tumor cell migration and invasion

NARCIS (Netherlands)

Sahlgren, C.; Gustafsson, M.V.; Jin, S.; Poellinger, L.; Lendahl, U.

2008-01-01

Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood. Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial-mesenchymal transition (EMT), increased motility, and

Comparative aspects of hypoxia tolerance of the ectothermic vertebrate heart

DEFF Research Database (Denmark)

Gesser, Hans; Overgaard, Johannes

2009-01-01

This chapter reviews cardiac contractile performance and its regulation during hypoxia/anoxia with regard to cellular metabolism and energy state, in particular hypoxia-tolerant ectothermic vertebrates. Overall the contractile performance of the hypoxic isolated heart muscle varies in a way...

Effect of low-frequency low-intensity ultrasound with microbubbles on prostate cancer hypoxia.

Science.gov (United States)

Hou, Rui; Xu, Yanjun; Lu, Qijie; Zhang, Yang; Hu, Bing

2017-10-01

Angiogenesis plays an important role in tumor growth, invasiveness, and metastasis. It is well established that prostate cancer is exposed to fluctuating oxygen tensions and both acute and chronic hypoxia exist, and these conditions can upregulate angiogenesis-associated proteins such as hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A. Low-frequency low-intensity ultrasound with microbubbles can induce obvious microvessel damage in tumors, cause cell necrosis or apoptosis. However, there is no information about whether the blocking blood effect of low-frequency low-intensity ultrasound with microbubbles has an influence on hypoxia environment of prostate cancer. Therefore, we investigated the impact of different low-frequency low-intensity ultrasound with microbubbles radiation times on prostate tumors, observed the change in the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A protein levels, as well as cell proliferation, apoptosis, and tumor volume. The results indicated that as the radiation was repeated four times on each treatment day, the effects of interruption were durable, the cell proliferation was inhibited, and apoptosis was promoted, and the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were lower in the treatment group than in the control group. When the radiation was carried out once per treatment day, the hypoxia response was stimulated, the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were higher compared with the control group, and cell proliferation was promoted. In addition, the tumor volume increased obviously in the hypoxia-stimulated group, whereas tumors grew slowly in the hypoxia-suppressed group. The results of this work demonstrated that under the same conditions, different radiation times of low-frequency low-intensity ultrasound with microbubbles affect the hypoxia response differently, and the

The Influence of CO2 and Exercise on Hypobaric Hypoxia Induced Pulmonary Edema in Rats

Directory of Open Access Journals (Sweden)

Ryan L. Sheppard

2018-02-01

Full Text Available Introduction: Individuals with a known susceptibility to high altitude pulmonary edema (HAPE demonstrate a reduced ventilation response and increased pulmonary vasoconstriction when exposed to hypoxia. It is unknown whether reduced sensitivity to hypercapnia is correlated with increased incidence and/or severity of HAPE, and while acute exercise at altitude is known to exacerbate symptoms the effect of exercise training on HAPE susceptibility is unclear.Purpose: To determine if chronic intermittent hypercapnia and exercise increases the incidence of HAPE in rats.Methods: Male Wistar rats were randomized to sedentary (sed-air, CO2 (sed-CO2, exercise (ex-air, or exercise + CO2 (ex-CO2 groups. CO2 (3.5% and treadmill exercise (15 m/min, 10% grade were conducted on a metabolic treadmill, 1 h/day for 4 weeks. Vascular reactivity to CO2 was assessed after the training period by rheoencephalography (REG. Following the training period, animals were exposed to hypobaric hypoxia (HH equivalent to 25,000 ft for 24 h. Pulmonary injury was assessed by wet/dry weight ratio, lung vascular permeability, bronchoalveolar lavage (BAL, and histology.Results: HH increased lung wet/dry ratio (HH 5.51 ± 0.29 vs. sham 4.80 ± 0.11, P < 0.05, lung permeability (556 ± 84 u/L vs. 192 ± 29 u/L, P < 0.001, and BAL protein (221 ± 33 μg/ml vs. 114 ± 13 μg/ml, P < 0.001, white blood cell (1.16 ± 0.26 vs. 0.66 ± 0.06, P < 0.05, and platelet (16.4 ± 2.3, vs. 6.0 ± 0.5, P < 0.001 counts in comparison to normobaric normoxia. Vascular reactivity was suppressed by exercise (−53% vs. sham, P < 0.05 and exercise+CO2 (−71% vs. sham, P < 0.05. However, neither exercise nor intermittent hypercapnia altered HH-induced changes in lung wet/dry weight, BAL protein and cellular infiltration, or pulmonary histology.Conclusion: Exercise training attenuates vascular reactivity to CO2 in rats but neither exercise training nor chronic intermittent hypercapnia affect HH- induced

Quantitative imaging of pO2 in orthotopic murine gliomas: hypoxia correlates with resistance to radiation.

Science.gov (United States)

Yasui, Hironobu; Kawai, Tatsuya; Matsumoto, Shingo; Saito, Keita; Devasahayam, Nallathamby; Mitchell, James B; Camphausen, Kevin; Inanami, Osamu; Krishna, Murali C

2017-10-01

Hypoxia is considered one of the microenvironmental factors associated with the malignant nature of glioblastoma. Thus, evaluating intratumoural distribution of hypoxia would be useful for therapeutic planning as well as assessment of its effectiveness during the therapy. Electron paramagnetic resonance imaging (EPRI) is an imaging technique which can generate quantitative maps of oxygen in vivo using the exogenous paramagnetic compound, triarylmethyl and monitoring its line broadening caused by oxygen. In this study, the feasibility of EPRI for assessment of oxygen distribution in the glioblastoma using orthotopic U87 and U251 xenograft model is examined. Heterogeneous distribution of pO 2 between 0 and 50 mmHg was observed throughout the tumours except for the normal brain tissue. U251 glioblastoma was more likely to exhibit hypoxia than U87 for comparable tumour size (median pO 2 ; 29.7 and 18.2 mmHg, p = .028, in U87 and U251, respectively). The area with pO 2 under 10 mmHg on the EPR oximetry (HF10) showed a good correlation with pimonidazole staining among tumours with evaluated size. In subcutaneous xenograft model, irradiation was relatively less effective for U251 compared with U87. In conclusion, EPRI is a feasible method to evaluate oxygen distribution in the brain tumour.

Role of hypoxia-inducible factor in diabetic myocardial hypertrophy ...

African Journals Online (AJOL)

Purpose: This study was carried out to investigate the role of hypoxia-inducible factor (HIF) in diabetic cardiomyopathy in vitro. Methods: Hypoxia was induced chemically in H9C2 cells (cardiac hypertrophy model), and the cells were treated with phenylephrine (PE), deferoxamine (DFO), PE + DFO, and HIF-1α siRNA under ...

Effect of acadesine on breast cancer cells under hypoxia

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A. M. Shcherbakov

2017-01-01

Full Text Available The riboside derivative acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside is currently being tested in clinical trials as a promising anti-tumor drug. Intracellular target of acadesine is adenosine monophosphate-activated protein kinase (АМРК, an important regulatory molecule of energy metabolism. It is expected that acadesine would be active in tumors under hypoxia conditions. In normoxia (cells incubated in 21 % oxygen, acadesine inhibited proliferation and induced cell death of breast adenocarcinoma, including the triple negative breast cancer line. When oxygen partial pressure was decreased to 1 % (experimental hypoxia, acadesine inhibited activation of reporter construct responsive to HIF-1α (hypoxia inducible factor 1 alpha transcription factor. This effect was observed for acadesine in concentrations close to cytotoxic. Acadesine retained cytotoxicity under hypoxia and decreased the survival of the MDA-MB-231 cell line when used in combination with cisplatin. These results considerably widen acadesine’s field of application and allow to assume its efficacy in chemotherapy combination regimens for breast cancer, including the tumors with low oxygenation.

Software licenses: Good fences make good neighbors

International Nuclear Information System (INIS)

McCreary, J.G.; Woodyard, A.

1995-01-01

The basis for a good contract is that it is beneficial to both parties. A good foundation will cement the responsibilities and obligations of the parties after areas of agreement have been negotiated. Unfortunately, software licenses do not always reflect what is best for all. Some clauses are definitely for the benefit of the vendor, while others are required by a prudent client. The resulting contract is then a matter of reasonable compromise to achieve a good business relationship. Major issues of warranty, liability, training, support, and payment may be in conflict. Such topics as maintenance, testing, patents, extent of use, and return of software are often overlooked or addressed unevenly. This paper addresses these subjects and provides guidelines for software licenses. An understanding of legal phrases is of value. A better understanding of the viewpoints of both the vendor and the client results in a better working relationship

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...

Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells

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Eugenia Mata-Greenwood

2017-05-01

Full Text Available Background : Hypoxia inducible factor 1 alpha (HIF1A is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia.Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen on human brain micro endothelial cells (HBMEC viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia.Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent.

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

Science.gov (United States)

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

2017-01-01

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

Chronic Intermittent Hypoxia Induces Atherosclerosis

OpenAIRE

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

2007-01-01

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

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.

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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Yoichi Takakusagi

Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

Science.gov (United States)

Takakusagi, Yoichi; Matsumoto, Shingo; Saito, Keita; Matsuo, Masayuki; Kishimoto, Shun; Wojtkowiak, Jonathan W; DeGraff, William; Kesarwala, Aparna H; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Munasinghe, Jeeva P; Gillies, Robert J; Mitchell, James B; Hart, Charles P; Krishna, Murali C

2014-01-01

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth. Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

Dynamics and distribution of natural and human-caused hypoxia

Science.gov (United States)

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

2010-02-01

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

Intermittent Hypoxia Alters Gene Expression in Peripheral Blood Mononuclear Cells of Healthy Volunteers.

Science.gov (United States)

Polotsky, Vsevolod Y; Bevans-Fonti, Shannon; Grigoryev, Dmitry N; Punjabi, Naresh M

2015-01-01

Obstructive sleep apnea is associated with high cardiovascular morbidity and mortality. Intermittent hypoxia of obstructive sleep apnea is implicated in the development and progression of insulin resistance and atherosclerosis, which have been attributed to systemic inflammation. Intermittent hypoxia leads to pro-inflammatory gene up-regulation in cell culture, but the effects of intermittent hypoxia on gene expression in humans have not been elucidated. A cross-over study was performed exposing eight healthy men to intermittent hypoxia or control conditions for five hours with peripheral blood mononuclear cell isolation before and after exposures. Total RNA was isolated followed by gene microarrays and confirmatory real time reverse transcriptase PCR. Intermittent hypoxia led to greater than two fold up-regulation of the pro-inflammatory gene toll receptor 2 (TLR2), which was not increased in the control exposure. We hypothesize that up-regulation of TLR2 by intermittent hypoxia may lead to systemic inflammation, insulin resistance and atherosclerosis in patients with obstructive sleep apnea.

The effect of hypobaric hypoxia on multichannel EEG signal complexity.

Science.gov (United States)

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

2007-01-01

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

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.

Antioxidant mechanism of Rutin on hypoxia-induced pulmonary arterial cell proliferation.

Science.gov (United States)

Li, Qian; Qiu, Yanli; Mao, Min; Lv, Jinying; Zhang, Lixin; Li, Shuzhen; Li, Xia; Zheng, Xiaodong

2014-11-18

Reactive oxygen species (ROS) are involved in the pathologic process of pulmonary arterial hypertension as either mediators or inducers. Rutin is a type of flavonoid which exhibits significant scavenging properties on oxygen radicals both in vitro and in vivo. In this study, we proposed that rutin attenuated hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation by scavenging ROS. Immunofluorescence data showed that rutin decreased the production of ROS, which was mainly generated through mitochondria and NADPH oxidase 4 (Nox4) in pulmonary artery endothelial cells (PAECs). Western blot results provided further evidence on rutin increasing expression of Nox4 and hypoxia-inducible factor-1α (HIF-1α). Moreover, cell cycle analysis by flow cytometry indicated that proliferation of PASMCs triggered by hypoxia was also repressed by rutin. However, N-acetyl-L-cysteine (NAC), a scavenger of ROS, abolished or diminished the capability of rutin in repressing hypoxia-induced cell proliferation. These data suggest that rutin shows a potential benefit against the development of hypoxic pulmonary arterial hypertension by inhibiting ROS, subsequently preventing hypoxia-induced PASMC proliferation.

Antioxidant Mechanism of Rutin on Hypoxia-Induced Pulmonary Arterial Cell Proliferation

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Qian Li

2014-11-01

Full Text Available Reactive oxygen species (ROS are involved in the pathologic process of pulmonary arterial hypertension as either mediators or inducers. Rutin is a type of flavonoid which exhibits significant scavenging properties on oxygen radicals both in vitro and in vivo. In this study, we proposed that rutin attenuated hypoxia-induced pulmonary artery smooth muscle cell (PASMC proliferation by scavenging ROS. Immunofluorescence data showed that rutin decreased the production of ROS, which was mainly generated through mitochondria and NADPH oxidase 4 (Nox4 in pulmonary artery endothelial cells (PAECs. Western blot results provided further evidence on rutin increasing expression of Nox4 and hypoxia-inducible factor-1α (HIF-1α. Moreover, cell cycle analysis by flow cytometry indicated that proliferation of PASMCs triggered by hypoxia was also repressed by rutin. However, N-acetyl-L-cysteine (NAC, a scavenger of ROS, abolished or diminished the capability of rutin in repressing hypoxia-induced cell proliferation. These data suggest that rutin shows a potential benefit against the development of hypoxic pulmonary arterial hypertension by inhibiting ROS, subsequently preventing hypoxia-induced PASMC proliferation.

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.

Modulation of Radioprotective Effects of Respiratory Hypoxia by Changing the Duration of Hypoxia before Irradiation and by Combining Hypoxia and Administration of Hemopoiesis-Stimulating Agents

Czech Academy of Sciences Publication Activity Database

Vacek, Antonín; Tačev, T.; Hofer, Michal

2001-01-01

Roč. 177, č. 9 (2001), s. 474-481 ISSN 0179-7158 Institutional research plan: CEZ:AV0Z5004920 Keywords : radioprotection * mice * hypoxia Subject RIV: BO - Biophysics Impact factor: 3.005, year: 2001

Structural and functional analysis of coral Hypoxia Inducible Factor.

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Didier Zoccola

Full Text Available Tissues of symbiotic Cnidarians are exposed to wide, rapid and daily variations of oxygen concentration. Indeed, during daytime, intracellular O2 concentration increases due to symbiont photosynthesis, while during night, respiration of both host cells and symbionts leads to intra-tissue hypoxia. The Hypoxia Inducible Factor 1 (HIF-1 is a heterodimeric transcription factor used for maintenance of oxygen homeostasis and adaptation to hypoxia. Here, we carried out a mechanistic study of the response to variations of O2 concentrations of the coral model Stylophora pistillata. In silico analysis showed that homologs of HIF-1 α (SpiHIF-1α and HIF-1β (SpiHIF-1β exist in coral. A specific SpiHIF-1 DNA binding on mammalian Hypoxia Response Element (HRE sequences was shown in extracts from coral exposed to dark conditions. Then, we cloned the coral HIF-1α and β genes and determined their expression and transcriptional activity. Although HIF-1α has an incomplete Oxygen-dependent Degradation Domain (ODD relative to its human homolog, its protein level is increased under hypoxia when tested in mammalian cells. Moreover, co-transfection of SpiHIF-1α and β in mammalian cells stimulated an artificial promoter containing HRE only in hypoxic conditions. This study shows the strong conservation of molecular mechanisms involved in adaptation to O2 concentration between Cnidarians and Mammals whose ancestors diverged about 1,200-1,500 million years ago.

Structural and functional analysis of coral Hypoxia Inducible Factor.

Science.gov (United States)

Zoccola, Didier; Morain, Jonas; Pagès, Gilles; Caminiti-Segonds, Natacha; Giuliano, Sandy; Tambutté, Sylvie; Allemand, Denis

2017-01-01

Tissues of symbiotic Cnidarians are exposed to wide, rapid and daily variations of oxygen concentration. Indeed, during daytime, intracellular O2 concentration increases due to symbiont photosynthesis, while during night, respiration of both host cells and symbionts leads to intra-tissue hypoxia. The Hypoxia Inducible Factor 1 (HIF-1) is a heterodimeric transcription factor used for maintenance of oxygen homeostasis and adaptation to hypoxia. Here, we carried out a mechanistic study of the response to variations of O2 concentrations of the coral model Stylophora pistillata. In silico analysis showed that homologs of HIF-1 α (SpiHIF-1α) and HIF-1β (SpiHIF-1β) exist in coral. A specific SpiHIF-1 DNA binding on mammalian Hypoxia Response Element (HRE) sequences was shown in extracts from coral exposed to dark conditions. Then, we cloned the coral HIF-1α and β genes and determined their expression and transcriptional activity. Although HIF-1α has an incomplete Oxygen-dependent Degradation Domain (ODD) relative to its human homolog, its protein level is increased under hypoxia when tested in mammalian cells. Moreover, co-transfection of SpiHIF-1α and β in mammalian cells stimulated an artificial promoter containing HRE only in hypoxic conditions. This study shows the strong conservation of molecular mechanisms involved in adaptation to O2 concentration between Cnidarians and Mammals whose ancestors diverged about 1,200-1,500 million years ago.

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: epigenetic regulation of the hypoxic response via hypoxia-inducible factor and histone modifying enzymes.

Science.gov (United States)

Mimura, Imari; Tanaka, Tetsuhiro; Wada, Youichiro; Kodama, Tatsuhiko; Nangaku, Masaomi

2011-01-01

The hypoxia response regulated primarily by hypoxia-inducible factor (HIF) influences metabolism, cell survival, and angiogenesis to maintain biological homeostasis. In addition to the traditional transcriptional regulation by HIF, recent studies have shown that epigenetic modulation such as histone methylation, acetylation, and DNA methylation could change the regulation of the response to hypoxia. Eukaryotic chromatin is known to be modified by multiple post-translational histone methylation and demethylation, which result in the chromatin conformation change to adapt to hypoxic stimuli. Interestingly, some of the histone demethylase enzymes, which have the Jumonji domain-containing family, require oxygen to function and are induced by hypoxia in an HIF-1-dependent manner. Recent studies have demonstrated that histone modifiers play important roles in the hypoxic environment such as that in cancer cells and that they may become new therapeutic targets for cancer patients. It may lead to finding a new therapy for cancer to clarify a new epigenetic mechanism by HIF and histone demethylase such as JMJD1A (KDM3A) under hypoxia.

Dynamics and distribution of natural and human-caused hypoxia

Directory of Open Access Journals (Sweden)

N. N. Rabalais

2010-02-01

Full Text Available Water masses can become undersaturated with oxygen when natural processes alone or in combination with anthropogenic processes produce enough organic carbon that is aerobically decomposed faster than the rate of oxygen re-aeration. The dominant natural processes usually involved are photosynthetic carbon production and microbial respiration. The re-supply rate is indirectly related to its isolation from the surface layer. Hypoxic water masses (<2 mg L⁻¹, or approximately 30% saturation can form, therefore, under "natural" conditions, and are more likely to occur in marine systems when the water residence time is extended, water exchange and ventilation are minimal, stratification occurs, and where carbon production and export to the bottom layer are relatively high. Hypoxia has occurred through geological time and naturally occurs in oxygen minimum zones, deep basins, eastern boundary upwelling systems, and fjords.

Hypoxia development and continuation in many areas of the world's coastal ocean is accelerated by human activities, especially where nutrient loading increased in the Anthropocene. This higher loading set in motion a cascading set of events related to eutrophication. The formation of hypoxic areas has been exacerbated by any combination of interactions that increase primary production and accumulation of organic carbon leading to increased respiratory demand for oxygen below a seasonal or permanent pycnocline. Nutrient loading is likely to increase further as population growth and resource intensification rises, especially with increased dependency on crops using fertilizers, burning of fossil fuels, urbanization, and waste water generation. It is likely that the occurrence and persistence of hypoxia will be even more widespread and have more impacts than presently observed.

Global climate change will further complicate the causative factors in both natural and human-caused hypoxia. The likelihood of

Acute effects of head-down tilt and hypoxia on modulators of fluid homeostasis

Science.gov (United States)

Whitson, P. A.; Cintron, N. M.; Pietrzyk, R. A.; Scotto, P.; Loeppky, J. A.

1994-01-01

In an effort to understand the interaction between acute postural fluid shifts and hypoxia on hormonal regulation of fluid homeostasis, the authors measured the responses to head-down tilt with and without acute exposure to normobaric hypoxia. Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), plasma aldosterone (ALD), and plasma renin activity (PRA) were measured in six healthy male volunteers who were exposed to a head-down tilt protocol during normoxia and hypoxia. The tilt protocol consisted of a 17 degrees head-up phase (30 minutes), a 28 degrees head-down phase (1 hour), and a 17 degrees head-up recovery period (2 hours, with the last hour normoxic in both experiments). Altitude equivalent to 14,828 ft was simulated by having the subjects breathe an inspired gas mixture with 13.9% oxygen. The results indicate that the postural fluid redistribution associated with a 60-minute head-down tilt induces the release of ANP and cGMP during both hypoxia and normoxia. Hypoxia increased cGMP, cAMP, ALD, and PRA throughout the protocol and significantly potentiated the increase in cGMP during head-down tilt. Hypoxia had no overall effect on the release of ANP, but appeared to attenuate the increase with head-down tilt. This study describes the acute effects of hypoxia on the endocrine response during fluid redistribution and suggests that the magnitude, but not the direction, of these changes with posture is affected by hypoxia.

Effect of hypoxia on tissue factor pathway inhibitor expression in breast cancer.

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Cui, X Y; Tinholt, M; Stavik, B; Dahm, A E A; Kanse, S; Jin, Y; Seidl, S; Sahlberg, K K; Iversen, N; Skretting, G; Sandset, P M

2016-02-01

ESSENTIALS: A hypoxic microenvironment is a common feature of tumors that may influence activation of coagulation. MCF-7 and SK-BR-3 breast cancer cells and breast cancer tissue samples were used. The results showed transcriptional repression of tissue factor pathway inhibitor expression in hypoxia. Hypoxia-inducible factor 1α may be a target for the therapy of cancer-related coagulation and thrombosis. Activation of coagulation is a common finding in patients with cancer, and is associated with an increased risk of venous thrombosis. As a hypoxic microenvironment is a common feature of solid tumors, we investigated the role of hypoxia in the regulation of tissue factor (TF) pathway inhibitor (TFPI) expression in breast cancer. To explore the transcriptional regulation of TFPI by hypoxia-inducible factor (HIF)-1α in breast cancer cells and their correlation in breast cancer tissues. MCF-7 and SK-BR-3 breast cancer cells were cultured in 1% oxygen or treated with cobalt chloride (CoCl2 ) to mimic hypoxia. Time-dependent and dose-dependent downregulation of TFPI mRNA (quantitative RT-PCR) and of free TFPI protein (ELISA) were observed in hypoxia. Western blotting showed parallel increases in the levels of HIF-1α protein and TF. HIF-1α inhibitor abolished or attenuated the hypoxia-induced downregulation of TFPI. Luciferase reporter assay showed that both hypoxia and HIF-1α overexpression caused strong repression of TFPI promoter activity. Subsequent chromatin immunoprecipitation and mutagenesis analysis demonstrated a functional hypoxia response element within the TFPI promoter, located at -1065 to -1060 relative to the transcriptional start point. In breast cancer tissue samples, gene expression analyses showed a positive correlation between the mRNA expression of TFPI and that of HIF-1α. This study demonstrates that HIF-1α is involved in the transcriptional regulation of the TFPI gene, and suggests that a hypoxic microenvironment inside a breast tumor may

PKA activity exacerbates hypoxia-induced ROS formation and hypoxic injury in PC-12 cells.

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Gozal, Evelyne; Metz, Cynthia J; Dematteis, Maurice; Sachleben, Leroy R; Schurr, Avital; Rane, Madhavi J

2017-09-05

Hypoxia is a primary factor in many pathological conditions. Hypoxic cell death is commonly attributed to metabolic failure and oxidative injury. cAMP-dependent protein kinase A (PKA) is activated in hypoxia and regulates multiple enzymes of the mitochondrial electron transport chain, thus may be implicated in cellular energy depletion and hypoxia-induced cell death. Wild type (WT) PC-12 cells and PKA activity-deficient 123.7 PC-12 cells were exposed to 3, 6, 12 and 24h hypoxia (0.1% or 5% O 2 ). Hypoxia, at 24h 0.1% O 2 , induced cell death and increased reactive oxygen species (ROS) in WT PC-12 cells. Despite lower ATP levels in normoxic 123.7 cells than in WT cells, hypoxia only decreased ATP levels in WT cells. However, menadione-induced oxidative stress similarly affected both cell types. While mitochondrial COX IV expression remained consistently higher in 123.7 cells, hypoxia decreased COX IV expression in both cell types. N-acetyl cysteine antioxidant treatment blocked hypoxia-induced WT cell death without preventing ATP depletion. Transient PKA catα expression in 123.7 cells partially restored hypoxia-induced ROS but did not alter ATP levels or COX IV expression. We conclude that PKA signaling contributes to hypoxic injury, by regulating oxidative stress rather than by depleting ATP levels. Therapeutic strategies targeting PKA signaling may improve cellular adaptation and recovery in hypoxic pathologies. Copyright © 2017 Elsevier B.V. All rights reserved.

Exercise performed at hypoxia influences mood state and anxiety symptoms

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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.

Hypoxia promotes tumor growth in linking angiogenesis to immune escape

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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.

The infectious hypoxia: occurrence and causes during Shigella infection.

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Arena, Ellen T; Tinevez, Jean-Yves; Nigro, Giulia; Sansonetti, Philippe J; Marteyn, Benoit S

2017-03-01

Hypoxia is defined as a tissue oxygenation status below physiological needs. During Shigella infection, an infectious hypoxia is induced within foci of infection. In this review, we discuss how Shigella physiology and virulence are modulated and how the main recruited immune cells, the neutrophils, adapt to this environment. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia.

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Stokes, Jennifer A; Arbogast, Tara E; Moya, Esteban A; Fu, Zhenxing; Powell, Frank L

2017-04-01

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, Pi O 2  = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( P minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia. NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory

Obstructive sleep apnea and cancer: effects of intermittent hypoxia?

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

2015-01-01

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

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

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Wang, Tian; Wang, Suping; Guo, Shirong; Sun, Yanjun

2006-09-01

With water culture, this paper studied the effects of exogenous spermidine (Spd) on the net photosynthetic rate (Pn), intercellular CO2 concentrations (Ci), stomatal conductance (Gs), transpiration rate (Tr), apparent quantum yield (phi c), and carboxylation efficiency (CE) of cucumber seedlings tinder hypoxia stress. The results showed that the Pn decreased gradually under hypoxia stress, and reached the minimum 10 days after by 63. 33% of the control. Compared with that of hypoxia-stressed plants, the Pn after 10 days application of exogenous Spd increased 1.25 times. A negative correlation (R2 = 0.4730 - 0.7118) was found between Pn and Ci. Gs and Tr changed in wider ranges, which decreased under hypoxia-stress, but increased under hypoxia-stress plus exogenous Spd application. There was a significant positive correlation between Gs and Tr (R2 = 0.7821 - 0.9458), but these two parameters had no significant correlation with Pn; Hypoxia stress induced a decrease of phi c and CE by 63.01% and 72.33%, respectively, while hypoxia stress plus exogenous Spd application made phi c and CE increase by 23% and 14%, respectively. The photo-inhibition of cucumber seedlings under hypoxia stress was mainly caused by non-stomatal limitation, while exogenous Spd alleviated the hypoxia stress by repairing photosynthesis system.

Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

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Helbig, Linda; Koi, Lydia; Brüchner, Kerstin; Gurtner, Kristin; Hess-Stumpp, Holger; Unterschemmann, Kerstin; Pruschy, Martin

2014-01-01

Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD 50 ) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P 50 , with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD 50 . Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation

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

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Wanchao Yang

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

Lead intoxication under environmental hypoxia impairs oral health.

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Terrizzi, Antonela R; Fernandez-Solari, Javier; Lee, Ching M; Martínez, María Pilar; Conti, María Ines

2014-01-01

We have reported that chronic lead intoxication under hypoxic environment induces alveolar bone loss that can lead to periodontal damage with the subsequent loss of teeth. The aim of the present study was to assess the modification of oral inflammatory parameters involved in the pathogenesis of periodontitis in the same experimental model. In gingival tissue, hypoxia increased inducible nitric oxid synthase (iNOS) activity (p lead decreased prostaglandin E2 (PGE2) content (p lead and PGE2 content was increased by both lead and hypoxia (p lead under hypoxic conditions. Results suggest a wide participation of inflammatory markers that mediate alveolar bone loss induced by these environmental conditions. The lack of information regarding oral health in lead-contaminated populations that coexist with hypoxia induced us to evaluate the alteration of inflammatory parameters in rat oral tissues to elucidate the link between periodontal damage and these environmental conditions.

Hypoxia signaling pathways: modulators of oxygen-related organelles

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Schönenberger, Miriam J.; Kovacs, Werner J.

2015-01-01

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

Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia

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Luciana Rodrigues Vieira

2015-04-01

Full Text Available Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA-on pancreatic expression of uncoupling protein-2 (UCP2, as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group or to a sham procedure (normoxia group. The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period. Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11. Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01. The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09 and 21% higher pancreatic β-cell function (p = 0.01. Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted.

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

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

2017-11-01

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

Hypoxia activates muscle-restricted coiled-coil protein (MURC) expression via transforming growth factor-β in cardiac myocytes.

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Shyu, Kou-Gi; Cheng, Wen-Pin; Wang, Bao-Wei; Chang, Hang

2014-03-01

The expression of MURC (muscle-restricted coiled-coil protein), a hypertrophy-regulated gene, increases during pressure overload. Hypoxia can cause myocardial hypertrophy; however, how hypoxia affects the regulation of MURC in cardiomyocytes undergoing hypertrophy is still unknown. The aim of the present study was to test the hypothesis that hypoxia induces MURC expression in cardiomyocytes during hypertrophy. The expression of MURC was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia and in an in vivo model of AMI (acute myocardial infarction) to induce myocardial hypoxia in adult rats. MURC protein and mRNA expression were significantly enhanced by hypoxia. MURC proteins induced by hypoxia were significantly blocked after the addition of PD98059 or ERK (extracellular-signal-regulated kinase) siRNA 30 min before hypoxia. Gel-shift assay showed increased DNA-binding activity of SRF (serum response factor) after hypoxia. PD98059, ERK siRNA and an anti-TGF-β (transforming growth factor-β) antibody abolished the SRF-binding activity enhanced by hypoxia or exogenous administration of TGF-β. A luciferase promoter assay demonstrated increased transcriptional activity of SRF in cardiomyocytes by hypoxia. Increased βMHC (β-myosin heavy chain) and BNP (B-type natriuretic peptide) protein expression and increased protein synthesis was identified after hypoxia with the presence of MURC in hypertrophic cardiomyocytes. MURC siRNA inhibited the hypertrophic marker protein expression and protein synthesis induced by hypoxia. AMI in adult rats also demonstrated increased MURC protein expression in the left ventricular myocardium. In conclusion, hypoxia in cultured rat neonatal cardiomyocytes increased MURC expression via the induction of TGF-β, SRF and the ERK pathway. These findings suggest that MURC plays a role in hypoxia-induced hypertrophy in cardiomyocytes.

Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo

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Vassiliki Kostourou

2004-07-01

Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

Molecular imaging of hypoxia in non-small-cell lung cancer

International Nuclear Information System (INIS)

Yip, Connie; Blower, Philip J.; Goh, Vicky; Landau, David B.; Cook, Gary J.R.

2015-01-01

Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility. (orig.)

Molecular imaging of hypoxia in non-small-cell lung cancer

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Yip, Connie [King' s College London, St Thomas' Hospital, Department of Cancer Imaging, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); National Cancer Centre, Department of Radiation Oncology, Singapore (Singapore); St Thomas' Hospital, Imaging 2, London (United Kingdom); Blower, Philip J. [King' s College London, St Thomas' Hospital, Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Goh, Vicky [King' s College London, St Thomas' Hospital, Department of Cancer Imaging, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); St Thomas' Hospital, Department of Radiology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Landau, David B. [King' s College London, St Thomas' Hospital, Department of Cancer Imaging, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); St Thomas' Hospital, Department of Clinical Oncology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Cook, Gary J.R. [King' s College London, St Thomas' Hospital, Department of Cancer Imaging, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); St Thomas' Hospital, Clinical PET Imaging Centre, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

2015-05-01

Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility. (orig.)

Normobaric Hypoxia and Submaximal Exercise Effects on Running Memory and Mood State in Women.

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Seo, Yongsuk; Gerhart, Hayden D; Stavres, Jon; Fennell, Curtis; Draper, Shane; Glickman, Ellen L

2017-07-01

An acute bout of exercise can improve cognitive function in normoxic and hypoxic conditions. However, limited research supports the improvement of cognitive function and mood state in women. The purpose of this study was to examine the effects of hypoxia and exercise on working memory and mood state in women. There were 15 healthy women (age = 22 ± 2 yr) who completed the Automated Neuropsychological Assessment Metrics-4th Edition (ANAM), including the Running Memory Continuous Performance Task (RMCPT) and Total Mood Disturbance (TMD) in normoxia (21% O2), at rest in normoxia and hypoxia (12.5% O2), and during cycling exercise at 60% and 40% Vo2max in hypoxia. RMCPT was not significantly impaired at 30 (100.3 ± 17.2) and 60 (96.6 ± 17.3) min rest in hypoxia compared to baseline in normoxia (97.0 ± 17.0). However, RMCPT was significantly improved during exercise (106.7 ± 20.8) at 60% Vo2max compared to 60 min rest in hypoxia. Following 30 (-89.4 ± 48.3) and 60 min of exposure to hypoxia (-79.8 ± 55.9) at rest, TMD was impaired compared with baseline (-107.1 ± 46.2). TMD was significantly improved during exercise (-108.5 ± 42.7) at 40% Vo2max compared with 30 min rest in hypoxia. Also, RMCPT was significantly improved during exercise (104.0 ± 19.1) at 60% Vo2max compared to 60 min rest in hypoxia (96.6 ± 17.3). Hypoxia and an acute bout of exercise partially influence RMCPT and TMD. Furthermore, a moderate-intensity bout of exercise (60%) may be a more potent stimulant for improving cognitive function than low-intensity (40%) exercise. The present data should be considered by aeromedical personnel performing cognitive tasks in hypoxia.Seo Y, Gerhart HD, Stavres J, Fennell C, Draper S, Glickman EL. Normobaric hypoxia and submaximal exercise effects on running memory and mood state in women. Aerosp Med Hum Perform. 2017; 88(7):627-632.

The tyrosine phosphatase SHP-1 regulates hypoxia inducible factor-1α (HIF-1α protein levels in endothelial cells under hypoxia.

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Stefan K Alig

Full Text Available The tyrosine phosphatase SHP-1 negatively influences endothelial function, such as VEGF signaling and reactive oxygen species (ROS formation, and has been shown to influence angiogenesis during tissue ischemia. In ischemic tissues, hypoxia induced angiogenesis is crucial for restoring oxygen supply. However, the exact mechanism how SHP-1 affects endothelial function during ischemia or hypoxia remains unclear. We performed in vitro endothelial cell culture experiments to characterize the role of SHP-1 during hypoxia.SHP-1 knock-down by specific antisense oligodesoxynucleotides (AS-Odn increased cell growth as well as VEGF synthesis and secretion during 24 hours of hypoxia compared to control AS-Odn. This was prevented by HIF-1α inhibition (echinomycin and apigenin. SHP-1 knock-down as well as overexpression of a catalytically inactive SHP-1 (SHP-1 CS further enhanced HIF-1α protein levels, whereas overexpression of a constitutively active SHP-1 (SHP-1 E74A resulted in decreased HIF-1α levels during hypoxia, compared to wildtype SHP-1. Proteasome inhibition (MG132 returned HIF-1α levels to control or wildtype levels respectively in these cells. SHP-1 silencing did not alter HIF-1α mRNA levels. Finally, under hypoxic conditions SHP-1 knock-down enhanced intracellular endothelial reactive oxygen species (ROS formation, as measured by oxidation of H2-DCF and DHE fluorescence.SHP-1 decreases half-life of HIF-1α under hypoxic conditions resulting in decreased cell growth due to diminished VEGF synthesis and secretion. The regulatory effect of SHP-1 on HIF-1α stability may be mediated by inhibition of endothelial ROS formation stabilizing HIF-1α protein. These findings highlight the importance of SHP-1 in hypoxic signaling and its potential as therapeutic target in ischemic diseases.

Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons.

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Malthankar-Phatak, Gauri H; Patel, Anant B; Xia, Ying; Hong, Soonsun; Chowdhury, Golam M I; Behar, Kevin L; Orina, Isaac A; Lai, James C K

2008-09-10

Mechanisms underlying hypoxia-induced neuronal adaptation have not been fully elucidated. In the present study we investigated glucose metabolism and the activities of glycolytic and TCA cycle enzymes in cerebro-cortical neurons exposed to hypoxia (3 days in 1% of O2) or normoxia (room air). Hypoxia led to increased activities of LDH (194%), PK (90%), and HK (24%) and decreased activities of CS (15%) and GDH (34%). Neurons were incubated with [1-(13)C]glucose for 45 and 120 min under normoxic or hypoxic (120 min only) conditions and 13C enrichment determined in the medium and cell extract using 1H-{13C}-NMR. In hypoxia-treated neurons [3-(13)C]lactate release into the medium was 428% greater than in normoxia-treated controls (45-min normoxic incubation) and total flux through lactate was increased by 425%. In contrast glucose oxidation was reduced significantly in hypoxia-treated neurons, even when expressed relative to total cellular protein, which correlated with the reduced activities of the measured mitochondrial enzymes. The results suggest that surviving neurons adapt to prolonged hypoxia by up-regulation of glycolysis and down-regulation of oxidative energy metabolism, similar to certain other cell types. The factors leading to adaptation and survival for some neurons but not others remain to be determined.

Alginate Microencapsulation of Human Islets Does Not Increase Susceptibility to Acute Hypoxia

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I. K. Hals

2013-01-01

Full Text Available Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1–0.3% O2 for 8 h, followed by reoxygenation on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8±3.5% in encapsulated and 42.9±5.2% in nonencapsulated islets (P<0.2. Nonencapsulated islets released 37.7% (median more HMGB1 compared to encapsulated islets after hypoxic culture conditions (P<0.001. Glucose-induced insulin release was marginally affected by hypoxia. Basal oxygen consumption was equally reduced in encapsulated and nonencapsulated islets, by 22.0±6.1% versus 24.8±5.7%. Among 27 tested cytokines/chemokines, hypoxia increased the secretion of IL-6 and IL-8/CXCL8 in both groups of islets, whereas an increase of MCP-1/CCL2 was seen only with nonencapsulated islets. Conclusion. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation.

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

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Li Chen

2015-01-01

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

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.

Hypoxia and the heart of poikilotherms

Czech Academy of Sciences Publication Activity Database

Ošťádal, Bohuslav

2014-01-01

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

Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: Evaluation using pattern recognition in microcirculatory supply units

International Nuclear Information System (INIS)

Maftei, Constantin-Alin; Bayer, Christine; Shi, Kuangyu; Astner, Sabrina T.; Vaupel, Peter

2011-01-01

Background and purpose: Evaluate changes in total hypoxia and hypoxia subtypes in vital tumor tissue of human head and neck squamous cell carcinomas (hHNSCC) upon fractionated irradiation. Materials and methods: Xenograft tumors were generated from 5 hHNSCC cell lines (UT-SCC-15, FaDu, SAS, UT-SCC-5 and UT-SCC-14). Hypoxia subtypes were quantified in cryosections based on (immuno-)fluorescent marker distribution patterns of Hoechst 33342 (perfusion), pimonidazole (hypoxia) and CD31 (endothelium) in microcirculatory supply units (MCSUs). Tumors were irradiated with 5 or 10 fractions of 2 Gy, 5×/week. Results: Upon irradiation with 10 fractions, the overall fraction of hypoxic MCSUs decreased in UT-SCC-15, FaDu and SAS, remained the same in UT-SCC-5 and increased in UT-SCC-14. Decreases were observed in the proportion of chronically hypoxic MCSUs in UT-SCC-15, in the fraction of acutely hypoxic MCSUs in UT-SCC-15 and SAS, and in the percentage of hypoxemically hypoxic MCSUs in SAS tumors. After irradiation with 5 fractions, there were no significant changes in hypoxia subtypes. Changes in the overall fraction of hypoxic MCSUs were comparable to corresponding alterations in the proportions of acutely hypoxic MCSUs. There was no correlation between radiation resistance (TCD 50 ) and any of the investigated hypoxic fractions upon fractionated irradiation. Conclusions: This study shows that there are large alterations in the fractions of hypoxia subtypes upon irradiation that can differ from changes in the overall fraction of hypoxic MCSUs.

A novel adjustable automated system for inducing chronic intermittent hypoxia in mice.

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Polšek, Dora; Bago, Marcel; Živaljić, Marija; Rosenzweig, Ivana; Lacza, Zsombor; Gajović, Srećko

2017-01-01

Sleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer's Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders. An automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8) and control mice (no hypoxia, n = 7) were handled in the same manner and their hippocampal brain regions compared by histology. The chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1) P apnea, which was validated by apoptosis of hippocampal neurons.

Lipid peroxidation in neonatal mouse brain subjected to two different types of hypoxia.

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Hasegawa, K; Yoshioka, H; Sawada, T; Nishikawa, H

1991-01-01

To elucidate the role of free radicals in the pathogenesis of neonatal hypoxic encephalopathy, we determined the content of thiobarbituric acid reactants (TBARs), as an index of lipid peroxidation related with a free radical reaction, in the brains of newborn mice during hypoxia and recovery from hypoxia. Hypoxic stress was induced by 100% nitrogen gas breathing (N2 group) or 100% carbon dioxide gas breathing (CO2 group). TBARs increased with 20 minutes of hypoxia and returned to the control level during the recovery period in both groups. The increase in TBARs in the CO2 group was greater than that in the N2 group. These results may suggest that free radical reaction occurs during the hypoxic period and that CO2 hypoxia is more effective on free radical production in the newborn brain than N2 hypoxia.

High-intensity Interval training enhances mobilization/functionality of endothelial progenitor cells and depressed shedding of vascular endothelial cells undergoing hypoxia.

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Tsai, Hsing-Hua; Lin, Chin-Pu; Lin, Yi-Hui; Hsu, Chih-Chin; Wang, Jong-Shyan

2016-12-01

Exercise training improves endothelium-dependent vasodilation, whereas hypoxic stress causes vascular endothelial dysfunction. Monocyte-derived endothelial progenitor cells (Mon-EPCs) contribute to vascular repair process by differentiating into endothelial cells. This study investigates how high-intensity interval (HIT) and moderate-intensity continuous (MCT) exercise training affect circulating Mon-EPC levels and EPC functionality under hypoxic condition. Sixty healthy sedentary males were randomized to engage in either HIT (3-min intervals at 40 and 80 % VO 2max for five repetitions, n = 20) or MCT (sustained 60 % VO 2max , n = 20) for 30 min/day, 5 days/week for 6 weeks, or to a control group (CTL) that did not received exercise intervention (n = 20). Mon-EPC characteristics and EPC functionality under hypoxic exercise (HE, 100 W under 12 % O 2 ) were determined before and after HIT, MCT, and CTL. The results demonstrated that after the intervention, the HIT group exhibited larger improvements in VO 2peak , estimated peak cardiac output (Q C ), and estimated peak perfusions of frontal cerebral lobe (Q FC ) and vastus lateralis (Q VL ) than the MCT group. Furthermore, HIT (a) increased circulating CD14 ++ /CD16 - /CD34 + /KDR + (Mon-1 EPC) and CD14 ++ /CD16 + /CD34 + /KDR + (Mon-2 EPC) cell counts, (b) promoted the migration and tube formation of EPCs, (c) diminished the shedding of endothelial (CD34 - /KDR + /phosphatidylserine + ) cells, and (d) elevated plasma nitrite plus nitrate, stromal cell-derived factor-1, matrix metalloproteinase-9, and vascular endothelial growth factor-A concentrations at rest or following HE, compared to those of MCT. In addition, Mon-1 and -2 EPC counts were directly related to VO 2peak and estimated peak Q C , Q FC , and Q VL . HIT is superior to MCT for improving hemodynamic adaptation and Mon-EPC production. Moreover, HIT effectively enhances EPC functionality and suppresses endothelial injury undergoing hypoxia.

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

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Mahendran Botlagunta

2011-03-01

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

Psychomotor skills learning under chronic hypoxia.

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

1999-09-29

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

Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice

International Nuclear Information System (INIS)

Yu, Lunyin; Hales, Charles A

2011-01-01

Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression in vivo. Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated. We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression in vitro, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na + -K + ATPase α1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1α and HIF2α) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na + -K + ATPase α1, c) increased HIF1α expression (no HIF2α was detected) and d) increased microvessel density in the tumor tissues. This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na + -K + ATPase was involved in hypoxic

Alginate Microencapsulation of Human Islets Does Not Increase Susceptibility to Acute Hypoxia

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Hals, I. K.; Rokstad, A. M.; Strand, B. L.; Oberholzer, J.; Grill, V.

2013-01-01

Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1–0.3% O2 for 8 h, followed by reoxygenation) on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8 ± 3.5% in encapsulated and 42.9 ± 5.2% in nonencapsulated islets (P microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation. PMID:24364039

Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells

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Adolf M. Sandbichler

2018-04-01

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

Temporal responses of coastal hypoxia to nutrient loading and physical controls

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W. M. Kemp

2009-12-01

Full Text Available The incidence and intensity of hypoxic waters in coastal aquatic ecosystems has been expanding in recent decades coincident with eutrophication of the coastal zone. Worldwide, there is strong interest in reducing the size and duration of hypoxia in coastal waters, because hypoxia causes negative effects for many organisms and ecosystem processes. Although strategies to reduce hypoxia by decreasing nutrient loading are predicated on the assumption that this action would reverse eutrophication, recent analyses of historical data from European and North American coastal systems suggest little evidence for simple linear response trajectories. We review published parallel time-series data on hypoxia and loading rates for inorganic nutrients and labile organic matter to analyze trajectories of oxygen (O₂ response to nutrient loading. We also assess existing knowledge of physical and ecological factors regulating O₂ in coastal marine waters to facilitate analysis of hypoxia responses to reductions in nutrient (and/or organic matter inputs. Of the 24 systems identified where concurrent time series of loading and O₂ were available, half displayed relatively clear and direct recoveries following remediation. We explored in detail 5 well-studied systems that have exhibited complex, non-linear responses to variations in loading, including apparent "regime shifts". A summary of these analyses suggests that O₂ conditions improved rapidly and linearly in systems where remediation focused on organic inputs from sewage treatment plants, which were the primary drivers of hypoxia. In larger more open systems where diffuse nutrient loads are more important in fueling O₂ depletion and where climatic influences are pronounced, responses to remediation tended to follow non-linear trends that may include hysteresis and time-lags. Improved understanding of hypoxia remediation requires that future studies use

Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

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Annika Bettina Foehrenbacher

2013-12-01

Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

Hypoxia Impacts on Food Web Linkages in a Pelagic Ecosystem

Science.gov (United States)

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

2016-02-01

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

Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain

NARCIS (Netherlands)

Biran, V.; Heine, V.M.; Verney, C.; Sheldon, R.A.; Spadafora, R.; Vexler, Z.S.; Rowitch, D.H.; Ferriero, D.M.

2011-01-01

Two-day-old (P2) rat pups were subjected to either a global hypoxia or to electrocoagulation of the right carotid artery followed by 2.5. h hypoxia. Cellular and regional injury in the cerebellum (CB) was studied at 1, 2 and 19. days using immunohistology. Following hypoxia and hypoxia-ischemia, all

Acute hypoxia limits endurance but does not affect muscle contractile properties.

NARCIS (Netherlands)

Degens, H.; Sanchez Horneros, J.M.; Hopman, M.T.E.

2006-01-01

Acute hypoxia causes skeletal muscle dysfunction in vitro, but little is known about its effect on muscle function in vivo. In 10 healthy male subjects, isometric contractile properties and fatigue resistance of the quadriceps muscle were determined during normoxia and hypoxia using electrically

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

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

2017-06-15

Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required. We analyse sixteen heterogeneous breast cancer cell-line transcriptomic datasets in hypoxia-related conditions collectively by employing the unique capabilities of the method, UNCLES, which integrates clustering results from multiple datasets and can address questions that cannot be answered by existing methods. This has been demonstrated by comparison with the state-of-the-art iCluster method. From this collection of genome-wide datasets include 15,588 genes, UNCLES identified a relatively high number of genes (>1000 overall) which are consistently co-regulated over all of the datasets, and some of which are still poorly understood and represent new potential HIF targets, such as RSBN1 and KIAA0195. Two main, anti-correlated, clusters were identified; the first is enriched with MYC targets participating in growth and proliferation, while the other is enriched with HIF targets directly participating in the hypoxia response. Surprisingly, in six clinical datasets, some sub-clusters of growth genes are found consistently positively correlated with hypoxia response genes, unlike the observation in cell lines. Moreover, the ability to predict bad prognosis by a combined signature of one sub-cluster of growth genes and one sub-cluster of hypoxia-induced genes appears to be comparable and perhaps greater than that of known

Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin

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Álvaro Vargas

2011-01-01

Full Text Available Hypobaric hypoxia is of interest due to an increase of human populations working at high altitude. Testicular damage is related to the physiological response (neoangiogenesis to increased intrascrotal blood flow as temperature rises. Hypoxia is a stress factor with overproduction of reactive oxygen species (ROS. The effect of hypoxia in mice reproductive parameters is analyzed. Animals were exposed to simulated hypoxia of 4,200 meters above sea level (m.a.s.l. in a chamber for 33.2 days, both to continuous (HH or intermittent hypoxia (HI with an intermittency period of 4 days hypoxia /4 days normoxia (500 m.a.s.l.. The anti-inflammatory drug Ibuprofen was administered to a group of mice to control vasodilation and increased blood flow. Melatonin was administered to another group of mice as a potent ROS scavenger. Animals in both HH and HI exposure were compared to normoxic non-treated controls. There was a hematological response in hypoxia, with an increase in hematocrit and reticulocytosis. There was also increased teratozoospermia. This damage was more pronounced in HH than HI, suggesting that alternating normoxic periods permits compensation for the effects of hypoxia. In both hypoxia systems, the level of lipoperoxidation and the instability of DNA increased. In HH, there was a reduction of teratozoospermia in melatonin-treated mice. Ibuprofen presented a protective effect on the same parameters as melatonin with both HI and HH. The quality of sperm DNA, fragmentation, unpacking and DNA stability diminished. In conclusion, reproductive damage elicited by HH or HI was partially ameliorated by simultaneous treatment with antiflogistic and/or antioxidant agents.

Stromal Expression of Hypoxia Regulated Proteins Is an Adverse Prognostic Factor in Colorectal Carcinomas

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Arjen H. G. Cleven

2007-01-01

Full Text Available Background: Hypoxia modifies the phenotype of tumors in a way that promotes tumor aggressiveness and resistance towards chemotherapy and radiotherapy. However, the expression and influence of hypoxia-regulated proteins on tumor biology are not well characterized in colorectal tumors. We studied the role of protein expression of hypoxia-inducible factor (HIF-1α, HIF-2α, carbonic anhydrase 9 (CA9 and glucose transporter 1 (GLUT1 in patients with colorectal adenocarcinomas. Methods: Expression of HIF-1α, HIF-2α, CA9 and GLUT1 was quantified by immunohistochemistry in 133 colorectal adenocarcinomas. The expression of hypoxia markers was correlated with clinicopathological variables and overall patient survival. Results: Expression of these hypoxia markers was detected in the epithelial compartment of the tumor cells as well as in tumor-associated stromal cells. Although tumor cells frequently showed expression of one or more of the investigated hypoxia markers, no correlation among these markers or with clinical response was found. However, within the tumor stroma, positive correlations between the hypoxia markers HIF-2α, CA9 and GLUT1 were observed. Furthermore expression of HIF-2α and CA9 in tumor-associated stroma were both associated with a significantly reduced overall survival. In the Cox proportional hazard model, stromal HIF-2α expression was an independent prognostic factor for survival. Conclusion: These observations show, that expression of hypoxia regulated proteins in tumor-associated stromal cells, as opposed to their expression in epithelial tumor cells, is associated with poor outcome in colorectal cancer. This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis.

Male fertility is reduced by chronic intermittent hypoxia mimicking sleep apnea in mice.

Science.gov (United States)

Torres, Marta; Laguna-Barraza, Ricardo; Dalmases, Mireia; Calle, Alexandra; Pericuesta, Eva; Montserrat, Josep M; Navajas, Daniel; Gutierrez-Adan, Alfonso; Farré, Ramon

2014-11-01

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and oxidative stress. However, it is unknown whether intermittent hypoxia mimicking OSA modifies male fertility. We tested the hypothesis that male fertility is reduced by chronic intermittent hypoxia mimicking OSA in a mouse model. Case-control comparison in a murine model. University research laboratory. Eighteen F1 (C57BL/6xCBA) male mice. Mice were subjected to a pattern of periodic hypoxia (20 sec at 5% O2 followed by 40 sec of room air) 6 h/day for 60 days or normoxia. After this period, mice performed a mating trial to determine effective fertility by assessing the number of pregnant females and fetuses. After euthanasia, oxidative stress in testes was assessed by measuring the expression of glutathione peroxidase 1 (Gpx1) and superoxide dismutase-1 (Sod1) by reverse-transcription polymerase chain reaction. Sperm motility was determined by Integrated Semen Analysis System (ISAS). Intermittent hypoxia significantly increased testicular oxidative stress, showing a reduction in the expression of Gpx1 and Sod1 by 38.9% and 34.4%, respectively, as compared with normoxia (P intermittent hypoxia group (P = 0.04). The proportion of pregnant females and number of fetuses per mating was significantly lower in the intermittent hypoxia group (0.33 ± 0.10 and 2.45 ± 0.73, respectively) than in normoxic controls (0.72 ± 0.16 and 5.80 ± 1.24, respectively). These results suggest that the intermittent hypoxia associated with obstructive sleep apnea (OSA) could induce fertility reduction in male patients with this sleep breathing disorder.

Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

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Toru Shibata

2002-01-01

Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

Preeclampsia, Hypoxia, Thrombosis, and Inflammation

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Amir A. Shamshirsaz

2012-01-01

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

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

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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 < 0.05) or in CHF-CBD animals (42 ± 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during 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. Copyright © 2015 the American Physiological Society.

Weakening of the radioprotective action of gas hypoxia with growth of ascitic tumors

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Aytmagambetova, B Z; Shmakova, N L; Fadeyeva, T A

1975-06-27

It was shown previously that moderate hypoxia induced by breathing oxygen-poor air (5 percent O/sub 2/) reduces the lethal effect of the total irradiation of mice, while with local irradiation of tumors reduction of tumor growth rate is even more marked in hypoxia-protected animals than with irradiation of mice in normal air. This suggests the possible therapeutic application of hypoxia. It was found that acute gas hypoxia strongly retards radiation damage to bone marrow, both qualitatively (type of cells affected) and quantitatively. In addition, a definite weakening of the protective effect of hypoxia was observed, this being proportional to increase in tumor size. Planned future tests involving direct dynamic measurement of oxygen stress as a function of amount of ascites are expected to supply further information on reduction of radiosensitivity of normal tissues and on the selective intensification of tumor regression. Graphic data accompany the paper. (JPRS)

Sympatho-adrenal activation by chronic intermittent hypoxia.

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Prabhakar, Nanduri R; Kumar, Ganesh K; Peng, Ying-Jie

2012-10-15

Recurrent apnea with chronic intermittent hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by hypoxia-inducible factor-1 and -2, respectively.

Hypoxia triggers high-altitude headache with migraine features: A prospective trial.

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Broessner, Gregor; Rohregger, Johanna; Wille, Maria; Lackner, Peter; Ndayisaba, Jean-Pierre; Burtscher, Martin

2016-07-01

Given the high prevalence and clinical impact of high-altitude headache (HAH), a better understanding of risk factors and headache characteristics may give new insights into the understanding of hypoxia being a trigger for HAH or even migraine attacks. In this prospective trial, we simulated high altitude (4500 m) by controlled normobaric hypoxia (FiO2 = 12.6%) to investigate acute mountain sickness (AMS) and headache characteristics. Clinical symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after six and 12 hours in hypoxia. O2 saturation was measured using pulse oximetry at the respective time points. History of primary headache, especially episodic or chronic migraine, was a strict exclusion criterion. In total 77 volunteers (43 (55.8%) males, 34 (44.2%) females) were enrolled in this study. Sixty-three (81.18%) and 40 (71.4%) participants developed headache at six or 12 hours, respectively, with height and SpO2 being significantly different between headache groups at six hours (p headache development (p headache according to the International Classification of Headache Disorders (ICHD-3 beta) in n = 5 (8%) or n = 6 (15%), at six and 12 hours, respectively. Normobaric hypoxia is a trigger for HAH and migraine-like headache attacks even in healthy volunteers without any history of migraine. Our study confirms the pivotal role of hypoxia in the development of AMS and beyond that suggests hypoxia may be involved in migraine pathophysiology. © International Headache Society 2015.

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates.

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Storz, Jay F; Scott, Graham R; Cheviron, Zachary A

2010-12-15

High-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high- and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.

Tourism. Leonardo da Vinci Series: Good Practices.

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Commission of the European Communities, Brussels (Belgium). Directorate-General for Education and Culture.

This brochure, part of a series about good practices in vocational training in the European Union, describes 10 projects that have promoted investment in human resources through training in the tourism sector to promote sustainable, or responsible, tourism. The projects and their countries of origin are as follows: (1) BEEFT, training of mobility…

Preventive effect of piracetam and vinpocetine on hypoxia-reoxygenation induced injury in primary hippocampal culture.

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Solanki, P; Prasad, D; Muthuraju, S; Sharma, A K; Singh, S B; Ilavzhagan, G

2011-04-01

The present study investigates the potential of Piracetam and Vinpocetine (nootropic drugs, known to possess neuroprotective properties) in preventing hypoxia-reoxygenation induced oxidative stress in primary hippocampal cell culture. The hippocampal culture was exposed to hypoxia (95% N(2), 5% CO(2)) for 3h and followed by 1h of reoxygenation (21% O(2) and 5% CO(2)) at 37 °C. The primary hippocampal cultures were supplemented with the optimum dose of Piracetam and Vinpocetine, independently, and the cultures were divided into six groups, viz. Control/Normoxia, Hypoxia, Hypoxia+Piracetam, Hypoxia+Vinpocetine, Normoxia + Piracetam and Normoxia+Vinpocetine. The cell-viability assays and biochemical oxidative stress parameters were evaluated for each of the six groups. Administration of 1mM Piracetam or 500 nM Vinpocetine significantly prevents the culture from hypoxia-reoxygenation injury when determined by Neutral Red assay, LDH release and Acetylcholine esterase activity. Results showed that Piracetam and Vinpocetine supplementation significantly prevented the fall of mitochondrial membrane potential, rise in ROS generation and reduction in antioxidant levels associated with the hypoxia-reoxygenation injury. In conclusion, the present study establishes that both Piracetam and Vinpocetine give neuroprotection against hypoxia-reoxygenation injury in primary hippocampal cell culture. Copyright © 2010 Elsevier Ltd. All rights reserved.

Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia.

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Jouett, Noah P; Moralez, Gilbert; Raven, Peter B; Smith, Michael L

2017-04-01

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in 1 ) SNA discharge and 2 ) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 ± 1.8, IHT: 24 ± 1.5, post-IHT 20.0 ± 1.3 bursts/min, all P 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT. NEW & NOTEWORTHY This study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients. Copyright © 2017 the American Physiological Society.

Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy

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Jiankai Zhang

2016-07-01

Full Text Available Background: Hypoxia is a well-known factor in the promotion of apoptosis, which contributes to the development of numerous cardiac diseases, such as heart failure and myocardial infarction. Inhibiting apoptosis is an important therapeutic strategy for the treatment of related heart diseases caused by ischemia/hypoxic injury. Previous studies have demonstrated that BAG3 plays an important role in cardiomyocyte apoptosis and survival. However, the role of BAG3 in hypoxia-induced cardiomyocyte apoptosis remains to be clarified. Here, we demonstrate that BAG3 is induced by hypoxia stimuli in cultured cardiomyocytes. Methods: BAG3 expression level was measured in H9c2 cells treated with hypoxia for 48 h. Cell proliferation and apoptosis were tested using MTT assay and Annexin V FITC-PI staining assay, respectively. The mRNA or protein expression level of BAG3, LC3-I, LC3-II, Atg5, NF-κB p65 and phosphorylated NF-κB p65 were assessed by qRT-PCR and western blot assay, respectively. Resluts: Overexpression of BAG3 inhibited cell apoptosis and promoted proliferation in hypoxia-injured H9c2 cells. Furthermore, autophagy and NF-κB were activated by BAG3 overexpression, and the NF-κB inhibitor PDTC could inhibit the activation of autophagy induced by BAG3 overexpression. In addition, the autophagy inhibitor 3-MA partly impeded the inhibitory effect of BAG3 on hypoxia-induced cardiomyocyte apoptosis. Conclusion: these results suggested that overexpression of BAG3 promoted cell proliferation and inhibited apoptosis by activating autophagy though the NF-κB signaling pathway in hypoxia-injured cardiomyocytes.

Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells

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Sørensen, Brita Singers; Busk, Morten; Olthof, Nadine; Speel, Ernst-Jan; Horsman, Michael R.; Alsner, Jan; Overgaard, Jens

2013-01-01

Background and purpose: HPV associated Head and Neck Squamous Cell Carcinoma (HNSCC) represents a distinct subgroup of HNSCC characterized by a favorable prognosis and a distinct molecular biology. Previous data from the randomized DAHANCA 5 trial indicated that HPV positive tumors did not benefit from hypoxic modifications by Nimorazole during radiotherapy, whereas a significant benefit was observed in the HPV negative tumors. However, more studies have demonstrated equal frequencies of hypoxic tumors among HPV-positive and HPV-negative tumors. The aim of the present study was to determine radiosensitivity, the impact of hypoxia and the effect of Nimorazole in HPV positive and HPV negative cell lines. Materials and method: The used cell lines were: UDSCC2, UMSCC47 and UPCISCC90 (HPV positive) and FaDu DD , UTSCC33 and UTSCC5 (HPV negative). Cells were cultured under normoxic or hypoxic conditions, and gene expression levels of previously established hypoxia induced genes were assessed by qPCR. Cells were irradiated with various doses under normoxia, hypoxia or hypoxia +1 mM Nimorazole, and the clonogenic survival was determined. Results: The HPV positive and HPV negative cell lines exhibited similar patterns of upregulation of hypoxia induced genes in response to hypoxia. The HPV positive cell lines were up to 2.4 times more radiation sensitive than HPV negative cell lines. However, all HPV positive cells displayed the same response to hypoxia in radiosensitivity, with an OER in the range 2.3–2.9, and a sensitizer effect of Nimorazole of 1.13–1.29, similar to HPV negative cells. Conclusions: Although HPV positive cells had a markedly higher radiosensitivity compared to HPV negative cells, they displayed the same relative radioresistance under hypoxia and the same relative sensitizer effect of Nimorazole. The clinical observation that HPV positive patients do not seem to benefit from Nimorazole treatment is not due to inherent differences in hypoxia sensitivity

Cytoprotective effects of atmospheric-pressure plasmas against hypoxia-induced neuronal injuries

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Yan, Xu; Meng, Zhaozhong; Ouyang, Jiting; Qiao, Yajun; Li, Jiaxin; Jia, Mei; Yuan, Fang; (Ken Ostrikov, Kostya

2018-02-01

Atmospheric pressure plasma jet (APPJ) has recently been the focus of cytoprotective research due to the physiological roles of ROS and RNS. In the current study, we investigated the effect of APPJ treatment on the hypoxia (1% oxygen) induced cell injuries. SH-SY5Y cells were treated by APPJ for different duration and incubated in normoxic condition (20% oxygen) for 5 h followed by 24 h hypoxia treatment. Cell viability was evaluated by lactate dehydrogenase (LDH) release and further monitored using the electric cell-substrate impedance sensing (ECIS) system after APPJ treatment. Results showed that APPJ could reduce cell injuries after 24 h hypoxia, which was consistent with the ECIS results. Furthermore, extracellular NO and H2O2 production was significantly increased with the APPJ treatment. It was also interesting to find that APPJ treatment reduced SH-SY5Y cells proliferation in the hypoxic microenvironment during the first 20 h of hypoxia. Although more work was still need to clarify whether the cell viability maintenance was related to the cell proliferation during hypoxia, our results provide the first evidence of real-time cell viability changes after APPJ treatment under both normoxic and hypoxic conditions, which could provide evidence for the neuroprotective applications of APPJ.

Translational control is a major contributor to hypoxia induced gene expression

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

2011-01-01

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

Loss aversion and hypoxia: less loss aversion in oxygen-depleted environment.

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Pighin, Stefania; Bonini, Nicolao; Savadori, Lucia; Hadjichristidis, Constantinos; Schena, Federico

2014-03-01

Hypoxia, the deprivation of adequate oxygen supply, constitutes a direct threat to survival by disrupting cardiovascular or respiratory homeostasis and eliciting a respiratory distress. Although hypoxia has been shown to increase brain vulnerability and impair basic cognitive functions, only one study has examined its effect on decision-making. The present study examined the effect of mild hypoxia on individual's loss aversion, that is, the tendency to be more affected by losses than equal sized gains. A sample of 26 participants were asked to either accept or reject a series of mixed gambles once in an oxygen-depleted environment (14.1% oxygen concentration) and once in a normoxic environment (20.9% oxygen concentration). Each gamble involved a 50-50 chance of winning or losing specified amounts of money. Mild hypoxia decreased loss aversion: on average in the normoxic condition participants accepted gambles if the gain was at least 2.4 times as large as the loss, whereas in the oxygen-depleted condition participants accepted gambles if the gain was at least 1.7 times as large as the loss. Mild hypoxia may push individuals to be less cautious in daily decisions that involve a trade-off between a gain and a loss.

Effect of superoxide anion scavenger on rat hearts with chronic intermittent hypoxia.

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Pai, Peiying; Lai, Ching Jung; Lin, Ching-Yuang; Liou, Yi-Fan; Huang, Chih-Yang; Lee, Shin-Da

2016-04-15

Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2 (-)-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNEL-positive apoptosis. The superoxide anion scavenger decreased hypoxia-induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis-inducing factor (AIF), and TUNEL-positive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances

Anesthesiology residents' perspective about good teaching--a qualitative needs assessment.

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Ortwein, Heiderose; Blaum, Wolf E; Spies, Claudia D

2014-01-01

Germany, like many other countries, will soon have a shortage of qualified doctors. One reason for the dissatisfaction amongst medical residents are the relatively unstructured residency training programs despite increasing importance of outcome-based education. The aim of our study was to identify characteristics and requirements for good teaching during anesthesiology residency training from the resident's point of view. A consensus workshop with residents from all medical universities in Germany was held. Participants were allocated to one of the three topics, chosen based on a 2009 nationwide evaluation of residency. The three topics were (A) characteristics of helpful/good teachers, (B) characteristics of helpful/good conditions and (C) characteristics of helpful/good curricular structure. Each group followed a nominal group technique consensus process to define and rank characteristics for a good residency. 31 (79.5%) resident representatives were present. The consented results put emphasis on the importance of structured curricula including transparent goals and objectives, in training formative assessments and quality assurance measures for the program. Residents further long for trained trainers with formal teaching qualifications and protected teaching time. Good residency training requires careful consideration of all stakeholders' needs. Results reflect and extend previous findings and are at least to some degree easily implemented. These findings are an important step to establish a broader consensus within the discipline.

Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer.

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Kim, Hak-Su; Wannatung, Tirawat; Lee, Sooho; Yang, Woo Kyeom; Chung, Sung Hyun; Lim, Jong-Seok; Choe, Wonchae; Kang, Insug; Kim, Sung-Soo; Ha, Joohun

2012-09-01

Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to chemotherapy failure and drug resistance. As an approach to target hypoxia, we assessed the potential of quercetin, a flavonoid widely distributed in plants, as a anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of AMP-activated protein kinase (AMPK). Quercetin significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system, quercetin more dramatically induced apoptosis of HCT116 cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under hypoxia, and a constitutively active form of AMPK effectively blocked quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role against hypoxia. Quercetin also reduced the activity of hypoxia-inducible factor-1 (HIF-1), a major transcription factor for adaptive cellular response to hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.

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

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Lorena Olivares-González

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

Hypoxia Aggravates Inactivity-Related Muscle Wasting

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Tadej Debevec

2018-05-01

Full Text Available Poor musculoskeletal state is commonly observed in numerous clinical populations such as chronic obstructive pulmonary disease (COPD and heart failure patients. It, however, remains unresolved whether systemic hypoxemia, typically associated with such clinical conditions, directly contributes to muscle deterioration. We aimed to experimentally elucidate the effects of systemic environmental hypoxia upon inactivity-related muscle wasting. For this purpose, fourteen healthy, male participants underwent three 21-day long interventions in a randomized, cross-over designed manner: (i bed rest in normoxia (NBR; PiO2 = 133.1 ± 0.3 mmHg, (ii bed rest in normobaric hypoxia (HBR; PiO2 = 90.0 ± 0.4 mmHg and ambulatory confinement in normobaric hypoxia (HAmb; PiO2 = 90.0 ± 0.4 mmHg. Peripheral quantitative computed tomography and vastus lateralis muscle biopsies were performed before and after the interventions to obtain thigh and calf muscle cross-sectional areas and muscle fiber phenotype changes, respectively. A significant reduction of thigh muscle size following NBR (-6.9%, SE 0.8%; P < 0.001 was further aggravated following HBR (-9.7%, SE 1.2%; P = 0.027. Bed rest-induced muscle wasting in the calf was, by contrast, not exacerbated by hypoxic conditions (P = 0.47. Reductions in both thigh (-2.7%, SE 1.1%, P = 0.017 and calf (-3.3%, SE 0.7%, P < 0.001 muscle size were noted following HAmb. A significant and comparable increase in type 2× fiber percentage of the vastus lateralis muscle was noted following both bed rest interventions (NBR = +3.1%, SE 2.6%, HBR = +3.9%, SE 2.7%, P < 0.05. Collectively, these data indicate that hypoxia can exacerbate inactivity-related muscle wasting in healthy active participants and moreover suggest that the combination of both, hypoxemia and lack of activity, as seen in COPD patients, might be particularly harmful for muscle tissue.

Extreme hypoxia tolerance of naked mole-rat brain.

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Larson, John; Park, Thomas J

2009-12-09

Mammalian brains have extremely high levels of aerobic metabolism and typically suffer irreversible damage after brief periods of oxygen deprivation such as occur during stroke or cardiac arrest. Here we report that brain tissue from naked mole-rats, rodents that live in a chronically low-oxygen environment, is remarkably resistant to hypoxia: naked mole-rat neurons maintain synaptic transmission much longer than mouse neurons and can recover from periods of anoxia exceeding 30 min. We suggest that brain tolerance to hypoxia may result from slowed or arrested brain development in these extremely long-lived animals.

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

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Malik Assaf

2012-11-01

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

Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

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Kathryn M. Buller

2012-01-01

Full Text Available Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

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

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Debora Coimbra-Costa

2017-08-01

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

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

INTRODUCTION: Hypoxia is associated with increased capillary permeability. This study tested whether acute hypobaric hypoxia involves degradation of the endothelial glycocalyx. METHODS: We exposed 12 subjects to acute hypobaric hypoxia (equivalent to 4500 m for 2-4 h) and measured venous blood...

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

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Deep, Gagan; Panigrahi, Gati K.

2017-01-01

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

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

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Septelia I. Wanandi

2011-02-01

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

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

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Deacon, Naomi L; McEvoy, R Doug; Stadler, Daniel L; Catcheside, Peter G

2017-09-01

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO 2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO 2 and 3.0 ± 0.2% O 2 ) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO 2 , O 2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea. NEW & NOTEWORTHY Both arousal state and concomitant CO 2 levels are known modulators of the effects of intermittent hypoxia on

Contribution of respiratory muscle blood flow to exercise-induced diaphragmatic fatigue in trained cyclists

DEFF Research Database (Denmark)

Vogiatzis, Ioannis; Athanasopoulos, Dimitris; Boushel, Robert Christopher

2008-01-01

We investigated whether the greater degree of exercise-induced diaphragmatic fatigue previously reported in highly trained athletes in hypoxia (compared with normoxia) could have a contribution from limited respiratory muscle blood flow. Seven trained cyclists completed three constant load 5 min...... exercise tests at inspired O(2) fractions (FIO2) of 0.13, 0.21 and 1.00 in balanced order. Work rates were selected to produce the same tidal volume, breathing frequency and respiratory muscle load at each FIO2 (63 +/- 1, 78 +/- 1 and 87 +/- 1% of normoxic maximal work rate, respectively). Intercostals......(-1) and 95.1 +/- 7.8 ml (100 ml)(-1) min(-1), respectively). Neither IMBF was different across hypoxia, normoxia and hyperoxia (53.6 +/- 8.5, 49.9 +/- 5.9 and 52.9 +/- 5.9 ml (100 ml)(-1) min(-1), respectively). We conclude that when respiratory muscle energy requirement is not different between...

Effect of perioperative fetal intrauterine hypoxia on maternal oxidative stress injury after cesarean section

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Xue-Hong Zou

2017-03-01

Full Text Available Objective: To study the effect of perioperative fetal intrauterine hypoxia on maternal oxidative stress injury after cesarean section. Methods: 37 puerperae receiving cesarean section for fetal intrauterine hypoxia between May 2014 and December 2016 were selected as hypoxia group and 40 puerperae receiving cesarean section during the same period and without complications during pregnancy or fetal intrauterine hypoxia were selected as control group. Umbilical arterial blood was collected after delivery of placenta for blood gas analysis, and the placenta tissue and serum samples were collected to test the content of oxidative stress products and antioxidants. Results: Umbilical arterial blood gas analysis parameters pH value as well as PO2, HCO3 - and BE content of hypoxia group were significantly lower than those of control group (P＜0.05; NADPH, reactive oxide species (ROS and reactive nitrogen species (RNS content in placenta tissue of hypoxia group were significantly higher than those of control group (P ＜0.05 while glutathione S-transferase (GST, glutathione peroxidase (GPx, superoxide dismutase (SOD, Trx, vitamin C (VitC, VitE and coenzyme Q10 (CoQ10 content were significantly lower than those of control group (P＜0.05; serum malondialdehyde (MDA and 8-iso-prostaglandin F2α (8-iso-PGF2α content of hypoxia group were significantly higher than those of control group (P＜0.05. Conclusions: Perioperative fetal intrauterine hypoxia can lead to maternal oxidative stress injury after cesarean section and increase the generation of free radicals and the consumption of antioxidants.

Prolonged hypoxia modulates platelet activating factor receptor-mediated responses by fetal ovine pulmonary vascular smooth muscle cells.

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Renteria, Lissette S; Raj, J Usha; Ibe, Basil O

2010-12-01

Hypoxia augments PAF receptor (PAFr) binding and PAFr protein expression in venous SMC (SMC-PV). We compared effect of acute and prolonged hypoxia (pO(2)<40 torr) on PAFr-mediated responses in arterial SMC (SMC-PA) and SMC-PV. Cells were studied for 30 min (acute) or for 48 h (prolonged) hypoxia and compared to normoxic (pO(2) ~100 torr) conditions. PAF binding was quantified in fmol/10(6) cells (mean ± SEM). PAF binding in normoxia were SMC-PA, 5.2 ± 0.2 and in SMC-PV, 19.3 ± 1.1; values in acute hypoxia were SMC-PA, 7.7 ± 0.4 and in SMC-PV, 27.8 ± 1.7. Prolonged hypoxia produced 6-fold increase in binding in SMC-PA, but only 2-fold increase in SMC-PV, but binding in SMC-PV was still higher. Acute hypoxia augmented inositol phosphate release by 50% and 40% in SMC-PA and SMC-PV, respectively. During normoxia, PAFr mRNA expression by both cell types was similar, but expression in hypoxia by SMC-PA was greater. In SMC-PA, hypoxia and PAF augmented intracellular calcium flux. Re-exposure of cells to 30 min normoxia after 48 h hypoxia decreased binding by 45-60%, suggesting immediate down-regulation of hypoxia-induced PAFr-mediated effects. We speculate that re-oxygenation immediately reverses hypoxia effect probably due to oxygen tension-dependent reversibility of PAFr activation and suggest that exposure of the neonate to prolonged state of hypoxia will vilify oxygen exchange capacity of the neonatal lungs. Copyright © 2010 Elsevier Inc. All rights reserved.

Guide to good practices for on-the-job training

Energy Technology Data Exchange (ETDEWEB)

1987-09-01

This manual is intended to provide DOE reactor and nonreactor nuclear facilities with guidelines for the development and implementation of facility specific, performance-based, On-the-Job Training (OJT) programs. An OJT Instructor Training Course is included to train the first-line supervisor and other designated personnel as OJT instructors. The subject matter content and level of detail were determined based upon a review of material obtained from DOE documents, INPO Guidelines, and input from selected DOE contractors. The final draft version of the manual was reviewed for accuracy, clarity, and comprehensiveness by trainers from the following DOE Contractors/Laboratories: Argonne National Laboratory - West - Idaho National Engineering Laboratory, E.I. DuPont - Savannah River Plant, EG and G Idaho, Inc. - Idaho National Engineering Laboratory, Los Alamos National Laboratory, Martin Marietta - Oak Ridge National Laboratory, Rockwell International - Rocky Flats Plant, and Westinghouse Hanford Co.

Normobaric Hypoxia Exposure during Low Altitude Stay and Performance of Elite-Level Race-Walkers

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Gaurav Sikri, AB Srinivasa

2016-06-01

Full Text Available We read with profound interest the article titled ‘Increased hypoxic dose after training at low altitude with 9h per night at 3000m normobaric hypoxia’ by Carr et al. (2015. Authors have concluded that low altitude (1380 m combined with normobaric hypoxia of 3000 m improves total haemoglobin mass (Hbmass and is an effective alternate method for training. Like other studies on elite athletes, the authors of present work have brought out that a major limitation was non-availability of a control group consisting of subjects undertaking same supervised training at normoxia. The total number of ‘possible’ subjects for control group which were taken from a previous study (Saunders et al., 2010 was 11 i.e placebo group (n = 6; 3 male and 3 female and Nocebo group (n = 5; 3 female and 2 male. It seems likely that authors of the present study have chosen only 10 subjects out of those 11. The criteria for exclusion of one subject and selection of 10 out of 11 subjects from the previous study to form the control group of the present study may require further elaboration.

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...

Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis.

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Gao, Wei; Sweeney, Catherine; Connolly, Mary; Kennedy, Aisling; Ng, Chin Teck; McCormick, Jennifer; Veale, Douglas J; Fearon, Ursula

2012-07-01

To examine the effect of hypoxia on Notch-1 signaling pathway components and angiogenesis in inflammatory arthritis. The expression and regulation of Notch-1, its ligand delta-like protein 4 (DLL-4) and downstream signaling components (hairy-related transcription factor 1 [HRT-1], HRT-2), and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions (1-3%) were assessed in synovial tissue specimens from patients with inflammatory arthritis and controls and in human dermal microvascular endothelial cells (HDMECs) by immunohistology, dual immunofluorescence staining (Notch-1/factor VIII), Western blotting, and real-time polymerase chain reaction. In vivo synovial tissue oxygen levels (tissue PO2) were measured under direct visualization at arthroscopy. HDMEC activation under hypoxic conditions in the presence of Notch-1 small interfering RNA (siRNA), the γ-secretase inhibitor DAPT, or dimethyloxalylglycine (DMOG) was assessed by Matrigel tube formation assay, migration assay, invasion assay, and matrix metalloproteinase 2 (MMP-2)/MMP-9 zymography. Expression of Notch-1, its ligand DLL-4, and HRT-1 was demonstrated in synovial tissue, with the strongest expression localized to perivascular/vascular regions. Localization of Notch-1 to synovial endothelium was confirmed by dual immunofluorescence staining. Notch-1 intracellular domain (NICD) expression was significantly higher in synovial tissue from patients with tissue PO2 of PO2 of >20 mm Hg (>3% O2). Exposure of HDMECs to 3% hypoxia induced HIF-1α and NICD protein expression and DLL-4, HRT-1, and HRT-2 messenger RNA expression. DMOG directly induced NICD expression, while Notch-1 siRNA inhibited hypoxia-induced HIF-1α expression, suggesting that Notch-1/HIF-1α signaling is bidirectional. Finally, 3% hypoxia-induced angiogenesis, endothelial cell migration, endothelial cell invasion, and proMMP-2 and proMMP-9 activities were inhibited by Notch-1 siRNA and/or the γ-secretase inhibitor DAPT. Our

Effects of hypoxia and ocean acidification on the upper thermal niche boundaries of coral reef fishes.

Science.gov (United States)

Ern, Rasmus; Johansen, Jacob L; Rummer, Jodie L; Esbaugh, Andrew J

2017-07-01

Rising ocean temperatures are predicted to cause a poleward shift in the distribution of marine fishes occupying the extent of latitudes tolerable within their thermal range boundaries. A prevailing theory suggests that the upper thermal limits of fishes are constrained by hypoxia and ocean acidification. However, some eurythermal fish species do not conform to this theory, and maintain their upper thermal limits in hypoxia. Here we determine if the same is true for stenothermal species. In three coral reef fish species we tested the effect of hypoxia on upper thermal limits, measured as critical thermal maximum (CT max ). In one of these species we also quantified the effect of hypoxia on oxygen supply capacity, measured as aerobic scope (AS). In this species we also tested the effect of elevated CO 2 (simulated ocean acidification) on the hypoxia sensitivity of CT max We found that CT max was unaffected by progressive hypoxia down to approximately 35 mmHg, despite a substantial hypoxia-induced reduction in AS. Below approximately 35 mmHg, CT max declined sharply with water oxygen tension ( P w O 2 ). Furthermore, the hypoxia sensitivity of CT max was unaffected by elevated CO 2 Our findings show that moderate hypoxia and ocean acidification do not constrain the upper thermal limits of these tropical, stenothermal fishes. © 2017 The Author(s).

HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells

International Nuclear Information System (INIS)

Liu, Junye; Zhang, Jing; Wang, Xiaowu; Li, Yan; Chen, Yongbin; Li, Kangchu; Zhang, Jian; Yao, Libo; Guo, Guozhen

2010-01-01

Hypoxia inducible factor 1 (HIF-1), the key mediator of hypoxia signaling pathways, has been shown involved in hypoxia-induced radioresistance. However, the underlying mechanisms are unclear. The present study demonstrated that both hypoxia and hypoxia mimetic cobalt chloride could increase the radioresistance of human cervical cancer Hela cells. Meanwhile, ectopic expression of HIF-1 could enhance the resistance of Hela cells to radiation, whereas knocking-down of HIF-1 could increase the sensitivity of Hela cells to radiation in the presence of hypoxia. N-Myc downstream-regulated gene 2 (NDRG2), a new HIF-1 target gene identified in our lab, was found to be upregulated by hypoxia and radiation in a HIF-1-dependent manner. Overexpression of NDRG2 resulted in decreased sensitivity of Hela cells to radiation while silencing NDRG2 led to radiosensitization. Moreover, NDRG2 was proved to protect Hela cells from radiation-induced apoptosis and abolish radiation-induced upregulation of Bax. Taken together, these data suggest that both HIF-1 and NDRG2 contribute to hypoxia-induced tumor radioresistance and that NDRG2 acts downstream of HIF-1 to promote radioresistance through suppressing radiation-induced Bax expression. It would be meaningful to further explore the clinical application potential of HIF-1 and NDRG2 blockade as radiosensitizer for tumor therapy.

Hypoxia modulates the differentiation potential of stem cells of the apical papilla.

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Vanacker, Julie; Viswanath, Aiswarya; De Berdt, Pauline; Everard, Amandine; Cani, Patrice D; Bouzin, Caroline; Feron, Olivier; Diogenes, Anibal; Leprince, Julian G; des Rieux, Anne

2014-09-01

Stem cells from the apical papilla (SCAP) are a population of mesenchymal stem cells likely involved in regenerative endodontic procedures and have potential use as therapeutic agents in other tissues. In these situations, SCAP are exposed to hypoxic conditions either within a root canal devoid of an adequate blood supply or in a scaffold material immediately after implantation. However, the effect of hypoxia on SCAP proliferation and differentiation is largely unknown. Therefore, the objective of this study was to evaluate the effect of hypoxia on the fate of SCAP. SCAP were cultured under normoxia (21% O2) or hypoxia (1% O2) in basal or differentiation media. Cellular proliferation, gene expression, differentiation, and protein secretion were analyzed by live imaging, quantitative reverse-transcriptase polymerase chain reaction, cellular staining, and enzyme-linked immunosorbent assay, respectively. Hypoxia had no effect on SCAP proliferation, but it evoked the up-regulation of genes specific for osteogenic differentiation (runt-related transcription factor 2, alkaline phosphatase, and transforming growth factor-β1), neuronal differentiation ( 2'-3'-cyclic nucleotide 3' phosphodiesterase, SNAIL, neuronspecific enolase, glial cell-derived neurotrophic factor and neurotrophin 3), and angiogenesis (vascular endothelial growth factor A and B). Hypoxia also increased the sustained production of VEGFa by SCAP. Moreover, hypoxia augmented the neuronal differentiation of SCAP in the presence of differentiation exogenous factors as detected by the up-regulation of NSE, VEGFB, and GDNF and the expression of neuronal markers (PanF and NeuN). This study shows that hypoxia induces spontaneous differentiation of SCAP into osteogenic and neurogenic lineages while maintaining the release of the proangiogenic factor VEGFa. This highlights the potential of SCAP to promote pulp-dentin regeneration. Moreover, SCAP may represent potential therapeutic agents for neurodegenerative

Prolonged hypoxia increases survival even in Zebrafish (Danio rerio showing cardiac arrhythmia.

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Renate Kopp

Full Text Available Tolerance towards hypoxia is highly pronounced in zebrafish. In this study even beneficial effects of hypoxia, specifically enhanced survival of zebrafish larvae, could be demonstrated. This effect was actually more pronounced in breakdance mutants, which phenotypically show cardiac arrhythmia. Breakdance mutants (bre are characterized by chronically reduced cardiac output. Despite an about 50% heart rate reduction, they become adults, but survival rate significantly drops to 40%. Normoxic bre animals demonstrate increased hypoxia inducible factor 1 a (Hif-1α expression, which indicates an activated hypoxic signaling pathway. Consequently, cardiovascular acclimation, like cardiac hypertrophy and increased erythrocyte concentration, occurs. Thus, it was hypothesized, that under hypoxic conditions survival might be even more reduced. When bre mutants were exposed to hypoxic conditions, they surprisingly showed higher survival rates than under normoxic conditions and even reached wildtype values. In hypoxic wildtype zebrafish, survival yet exceeded normoxic control values. To specify physiological acclimation, cardiovascular and metabolic parameters were measured before hypoxia started (3 dpf, when the first differences in survival rate occurred (7 dpf and when survival rate plateaued (15 dpf. Hypoxic animals expectedly demonstrated Hif-1α accumulation and consequently enhanced convective oxygen carrying capacity. Moreover, bre animals showed a significantly enhanced heart rate under hypoxic conditions, which reached normoxic wildtype values. This improvement in convective oxygen transport ensured a sufficient oxygen and nutrient supply and was also reflected in the significantly higher mitochondrial activity. The highly optimized energy metabolism observed in hypoxic zebrafish larvae might be decisive for periods of higher energy demand due to organ development, growth and increased activity. However, hypoxia increased survival only during a

Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy.

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Zhang, Jiankai; He, Zhangyou; Xiao, Wenjian; Na, Qingqing; Wu, Tianxiu; Su, Kaixin; Cui, Xiaojun

2016-01-01

Hypoxia is a well-known factor in the promotion of apoptosis, which contributes to the development of numerous cardiac diseases, such as heart failure and myocardial infarction. Inhibiting apoptosis is an important therapeutic strategy for the treatment of related heart diseases caused by ischemia/hypoxic injury. Previous studies have demonstrated that BAG3 plays an important role in cardiomyocyte apoptosis and survival. However, the role of BAG3 in hypoxia-induced cardiomyocyte apoptosis remains to be clarified. Here, we demonstrate that BAG3 is induced by hypoxia stimuli in cultured cardiomyocytes. BAG3 expression level was measured in H9c2 cells treated with hypoxia for 48 h. Cell proliferation and apoptosis were tested using MTT assay and Annexin V FITC-PI staining assay, respectively. The mRNA or protein expression level of BAG3, LC3-I, LC3-II, Atg5, NF-x03BA;B p65 and phosphorylated NF-x03BA;B p65 were assessed by qRT-PCR and western blot assay, respectively. Resluts: Overexpression of BAG3 inhibited cell apoptosis and promoted proliferation in hypoxia-injured H9c2 cells. Furthermore, autophagy and NF-x03BA;B were activated by BAG3 overexpression, and the NF-x03BA;B inhibitor PDTC could inhibit the activation of autophagy induced by BAG3 overexpression. In addition, the autophagy inhibitor 3-MA partly impeded the inhibitory effect of BAG3 on hypoxia-induced cardiomyocyte apoptosis. these results suggested that overexpression of BAG3 promoted cell proliferation and inhibited apoptosis by activating autophagy though the NF-x03BA;B signaling pathway in hypoxia-injured cardiomyocytes. © 2016 The Author(s) Published by S. Karger AG, Basel.

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

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2006-01-01

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

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

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Zhou Z

2016-04-01

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

[Hypoxia and memory. Specific features of nootropic agents effects and their use].

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Voronina, T A

2000-01-01

Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

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

Science.gov (United States)

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

2018-01-01

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

Living high-training low: effect on erythropoiesis and aerobic performance in highly-trained swimmers

DEFF Research Database (Denmark)

Robach, P.; Schmitt, L.; Brugniaux, J.V.

2006-01-01

LHTL enhances aerobic performance in athletes, and if any positive effect may last for up to 2 weeks after LHTL intervention. Eighteen swimmers trained for 13 days at 1,200 m while sleeping/living at 1,200 m in ambient air (control, n=9) or in hypoxic rooms (LHTL, n=9, 5 days at simulated altitude of 2......The "living high-training low" model (LHTL), i.e., training in normoxia but sleeping/living in hypoxia, is designed to improve the athletes performance. However, LHTL efficacy still remains controversial and also little is known about the duration of its potential benefit. This study tested whether......,500 m followed by 8 days at simulated altitude of 3,000 m, 16 h day(-1)). Measures were done before 1-2 days (POST-1) and 2 weeks after intervention (POST-15). Aerobic performance was assessed from two swimming trials, exploring .VO(2max) and endurance performance (2,000-m time trial), respectively...

Coastal change and hypoxia in the northern Gulf of Mexico: Part I

Directory of Open Access Journals (Sweden)

2007-01-01

Full Text Available The Committee on Environment and Natural Resources (CENR has identified the input of nutrient-rich water from the Mississippi/Atchafalaya River Basin (MARB as the prime cause of hypoxia in the northern Gulf of Mexico and the prime means for its control. A Watershed Nutrient Task Force was formed to solve the hypoxia problem by managing the MARB catchment. However, the hypoxic zone is also experiencing massive physical, hydrological, chemical and biological changes associated with an immense river-switching and delta-building event that occurs here about once a millennium. Coastal change induced hypoxia in the northern Gulf of Mexico prior to European settlement. It is recommended that for further understanding and control of Gulf hypoxia the Watershed Nutrient Task Force adopt a truly holistic environmental approach which includes the full effects of this highly dynamic coastal area.

Marine modification of terrestrial influences on Gulf hypoxia: Part II

Directory of Open Access Journals (Sweden)

2007-01-01

Full Text Available This study examines potential marine modification of two classes of terrestrial influence on Gulf hypoxia: (1 the flow of nutrient-rich water from the Mississippi/Atchafalaya River Basin and (2 the massive physical, hydrological, chemical and biological change associated with the Atchafalaya’s partial capture of the Mississippi River. The latter involves repartitioning of a total flow of about 20 000 m3 sec−1, equal to that of 13 Nile Rivers, and a sediment load of 210 million metric tonnes yr−1,nearly 20 times that delivered by all of the rivers of the East Coast of the USA. Also involved is the loss of hundreds-to-thousands of years of stored nutrients and organic matter to the Gulf from enormous coastal wetland loss. This study found that the oceanography of the Gulf minimises the impact of both classes of terrestrial influence from the Mississippi River and its nearby estuaries on Gulf hypoxia. Oceanographic conditions give events associated with the Atchafalaya River a disproportionately large influence on Gulf hypoxia. A truly holistic environmental approach which includes the full effects of this highly dynamic coastal area is recommended to better understand and control Gulf hypoxia.

Developmental programming of O2 sensing by neonatal intermittent hypoxia via epigenetic mechanisms

OpenAIRE

Nanduri, Jayasri; Prabhakar, Nanduri R.

2012-01-01

Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in infants born preterm. Carotid body chemo-reflex and catecholamine secretion from adrenal medullary chromaffin cells (AMC) are important for maintenance of cardio-respiratory homeostasis during hypoxia. This article highlights studies on the effects of IH on O2 sensing by the carotid body and AMC in neonatal rodents. Neonatal IH augments hypoxia-evoked carotid body sensory excitation and catecholamine secretion from ...

Intermittent Hypoxia in Childhood: The Harmful Consequences Versus Potential Benefits of Therapeutic Uses

OpenAIRE

Serebrovskaya, Tatiana V.; Xi, Lei

2015-01-01

Intermittent hypoxia often occurs in early infancy in both preterm and term infants and especially at 36 to 44 weeks postmenstrual age. These episodes of intermittent hypoxia could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of intermittent hypoxia on development, behavior, academic achievement and cognition in children with sleep apnea syndrome. It remains uncertain the exact causa...

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

Science.gov (United States)

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

2009-08-06

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

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

International Nuclear Information System (INIS)

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

2009-01-01

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

Is decision making in hypoxia affected by pre-acclimatisation? A randomized controlled trial.

Science.gov (United States)

Niedermeier, Martin; Weisleitner, Andreas; Lamm, Claus; Ledochowski, Larissa; Frühauf, Anika; Wille, Maria; Burtscher, Martin; Kopp, Martin

2017-05-01

Decision making is impaired in hypoxic environments, which may have serious or even lethal consequences for mountaineers. An acclimatisation period prior to high altitude exposures may help to overcome adverse effects of hypoxia. Thus, we investigated possible effects of short-term pre-acclimatisation on decision making in hypoxia. In a randomized controlled study design, 52 healthy participants were allocated to a hypoxia group (HG: short-term pre-acclimatisation by the use of intermittent hypoxia 7×1h at F i O 2 =12.6%, equivalent to 4500m) or a control group (CG: sham pre-acclimatisation 7×1h at F i O 2 =20.9%, equivalent to 600m). The number of risky decisions was assessed using the Game of Dice Task at four time points during a 12-hours stay in hypoxia (F i O 2 =12.6%). 42 (HG: 27, CG: 25) participants completed the study. The number of risky decisions was significantly (p=0.048 as determined by 4×2 ANCOVA) reduced in the hypoxia group compared to the control group, partial η 2 =0.11, when the age-effect on decision making was controlled. Self-reported positive affective valence prior to decision making was negatively related to the number of risky decisions, rdecision making in hypoxia in a positive way and might be considered as a risk-reducing preparation method prior to exposures to hypoxic environments. Positive affective states seem to have a medium-sized protective effect against risky decision making. Copyright © 2017 Elsevier Inc. All rights reserved.

Determination of the dynamics of tumor hypoxia during radiation therapy using biological imaging on mouse xenograft tumors

OpenAIRE

Maftei, Constantin Alin

2013-01-01

Background: Chronic, acute and hypoxemic hypoxia can lead to resistance to radiation therapy. The purpose of this thesis was to shed light on the role of these three hypoxia subtypes in radiotherapy. Methods: The amount of total hypoxia and hypoxia subtypes were assessed ex-vivo in xenograft tumors via (immuno-)fluorescence and H&E staining. For the non-invasive detection of hypoxia, tumor-bearing mice were injected with 18F-FMISO and underwent a dynamic PET/CT scan. The hypoxic fraction ...

Hyperglycemia Induces Cellular Hypoxia through Production of Mitochondrial ROS Followed by Suppression of Aquaporin-1.

Science.gov (United States)

Sada, Kiminori; Nishikawa, Takeshi; Kukidome, Daisuke; Yoshinaga, Tomoaki; Kajihara, Nobuhiro; Sonoda, Kazuhiro; Senokuchi, Takafumi; Motoshima, Hiroyuki; Matsumura, Takeshi; Araki, Eiichi

2016-01-01

We previously proposed that hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) generation is a key event in the development of diabetic complications. Interestingly, some common aspects exist between hyperglycemia and hypoxia-induced phenomena. Thus, hyperglycemia may induce cellular hypoxia, and this phenomenon may also be involved in the pathogenesis of diabetic complications. In endothelial cells (ECs), cellular hypoxia increased after incubation with high glucose (HG). A similar phenomenon was observed in glomeruli of diabetic mice. HG-induced cellular hypoxia was suppressed by mitochondria blockades or manganese superoxide dismutase (MnSOD) overexpression, which is a specific SOD for mtROS. Overexpression of MnSOD also increased the expression of aquaporin-1 (AQP1), a water and oxygen channel. AQP1 overexpression in ECs suppressed hyperglycemia-induced cellular hypoxia, endothelin-1 and fibronectin overproduction, and apoptosis. Therefore, hyperglycemia-induced cellular hypoxia and mtROS generation may promote hyperglycemic damage in a coordinated manner.