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Sample records for hypoxia modulates early

  1. Wavelength-Modulated Differential Photoacoustic Spectroscopy (WM-DPAS) for noninvasive early cancer detection and tissue hypoxia monitoring.

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    Choi, Sung Soo Sean; Mandelis, Andreas; Guo, Xinxin; Lashkari, Bahman; Kellnberger, Stephan; Ntziachristos, Vasilis

    2016-04-01

    This study introduces a novel noninvasive differential photoacoustic method, Wavelength Modulated Differential Photoacoustic Spectroscopy (WM-DPAS), for noninvasive early cancer detection and continuous hypoxia monitoring through ultrasensitive measurements of hemoglobin oxygenation levels (StO2 ). Unlike conventional photoacoustic spectroscopy, WM-DPAS measures simultaneously two signals induced from square-wave modulated laser beams at two different wavelengths where the absorption difference between maximum deoxy- and oxy-hemoglobin is 680 nm, and minimum (zero) 808 nm (the isosbestic point). The two-wavelength measurement efficiently suppresses background, greatly enhances the signal to noise ratio and thus enables WM-DPAS to detect very small changes in total hemoglobin concentration (CHb ) and oxygenation levels, thereby identifying pre-malignant tumors before they are anatomically apparent. The non-invasive nature also makes WM-DPAS the best candidate for ICU bedside hypoxia monitoring in stroke patients. Sensitivity tunability is another special feature of the technology: WM-DPAS can be tuned for different applications such as quick cancer screening and accurate StO2 quantification by selecting a pair of parameters, signal amplitude ratio and phase shift. The WM-DPAS theory has been validated with sheep blood phantom measurements. Sensitivity comparison between conventional single-ended signal and differential signal.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  3. Quantitative phase-filtered wavelength-modulated differential photoacoustic radar tumor hypoxia imaging toward early cancer detection.

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    Dovlo, Edem; Lashkari, Bahman; Soo Sean Choi, Sung; Mandelis, Andreas; Shi, Wei; Liu, Fei-Fei

    2016-10-19

    Overcoming the limitations of conventional linear spectroscopy used in multispectral photoacoustic imaging, wherein a linear relationship is assumed between the absorbed optical energy and the absorption spectra of the chromophore at a specific location, is crucial for obtaining accurate spatially-resolved quantitative functional information by exploiting known chromophore-specific spectral characteristics. This study introduces a non-invasive phase-filtered differential photoacoustic technique, wavelength-modulated differential photoacoustic radar (WM-DPAR) imaging that addresses this issue by eliminating the effect of the unknown wavelength-dependent fluence. It employs two laser wavelengths modulated out-of-phase to significantly suppress background absorption while amplifying the difference between the two photoacoustic signals. This facilitates pre-malignant tumor identification and hypoxia monitoring, as minute changes in total hemoglobin concentration and hemoglobin oxygenation are detectable. The system can be tuned for specific applications such as cancer screening and SO2 quantification by regulating the amplitude ratio and phase shift of the signal. The WM-DPAR imaging of a head and neck carcinoma tumor grown in the thigh of a nude rat demonstrates the functional PA imaging of small animals in vivo. The PA appearance of the tumor in relation to tumor vascularity is investigated by immunohistochemistry. Phase-filtered WM-DPAR imaging is also illustrated, maximizing quantitative SO2 imaging fidelity of tissues. Oxygenation levels within a tumor grown in the thigh of a nude rat using the two-wavelength phase-filtered differential PAR method.

  4. Modulation of hydrogen sulfide by vascular hypoxia

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    Osmond JM

    2014-08-01

    Full Text Available Jessica M Osmond, Nancy L KanagyVascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USAAbstract: Hydrogen sulfide (H2S has emerged as a key regulator of cardiovascular function. This gasotransmitter is produced in the vasculature and is involved in numerous processes that promote vascular homeostasis, including vasodilation and endothelial cell proliferation. Although H2S plays a role under physiological conditions, it has become clear in recent years that hypoxia modulates the production and action of H2S. Furthermore, there is growing evidence that H2S is cytoprotective in the face of hypoxic insults. This review focuses on the synthesis and signaling of H2S in hypoxic conditions in the vasculature, and highlights recent studies providing evidence that H2S is a potential therapy for preventing tissue damage in hypoxic conditions.Keywords: H2S, cystathionine γ-lyase, vascular smooth muscle, endothelium

  5. Human skin hypoxia modulates cerebrovascular and autonomic functions.

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    Olivia Pucci

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

  6. Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis.

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

    2015-01-01

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

  7. [Salidroside inhibits hypoxia-induced phenotypic modulation of corpus cavernosum smooth muscle cells in vitro].

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    Chen, Gang; Huang, Xiao-Jun; Lü, Bo-Dong; Chen, Shi-Tao; Zhang, Shi-Geng; Yang, Ke-Bing

    2013-08-01

    To explore the effects of salidroside on the phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMC) in hypoxic SD rats. CCSMCs were cultured in vitro and identified by immunohistochemistry. The cells were divided into six groups: normal control (21% O2), hypoxia (1% O2), hypoxia + salidroside 1 mg/L, hypoxia + salidroside 3 mg/L, hypoxia + salidroside 5 mg/L and hypoxia + PGE1 0.4 microg/L, and then cultured for 48 hours. The relative expressions of alpha-actin and osteopontin (OPN) in each group were determined by RT-PCR. The in vitro cultured CCSMCs grew well, with anti-alpha-smooth muscle actin monoclonal antibodies immunohistochemically positive. The relative expression of alpha-actin was markedly decreased while that of OPN remarkably increased in the hypoxia group as compared with the normal control group (P salidroside 5 mg/L group showed a significantly higher expression of alpha-actin and lower expression of OPN than the hypoxia group (P 0.05). Hypoxia can reduce the relative expression level of alpha-actin and increase that of OPN in the CCSMCs of SD rats, namely, induce their phenotypic modulation from the contraction to the non-contraction type. Salidroside can restrain hypoxia-induced phenotypic modulation of CCSMCs, and its inhibitory effect at 5 mg/L is similar to that of PGE1.

  8. Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.

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    Kohnoh, Takashi; Hashimoto, Naozumi; Ando, Akira; Sakamoto, Koji; Miyazaki, Shinichi; Aoyama, Daisuke; Kusunose, Masaaki; Kimura, Motohiro; Omote, Norihito; Imaizumi, Kazuyoshi; Kawabe, Tsutomu; Hasegawa, Yoshinori

    2016-01-01

    Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. Our study strengthens the therapeutic possibility that

  9. Hypoxia-induced down-modulation of PKCepsilon promotes trail-mediated apoptosis of tumor cells.

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    Gobbi, Giuliana; Masselli, Elena; Micheloni, Cristina; Nouvenne, Antonio; Russo, Domenico; Santi, Patrizia; Matteucci, Alessandro; Cocco, Lucio; Vitale, Marco; Mirandola, Prisco

    2010-09-01

    Tumor oxygen status is considered as a prognostic marker that impacts on malignant progression and outcome of tumor therapy. TNF-related apoptosis inducing ligand (TRAIL) plays a key role in cancer immunity, with potential applications in cancer therapy. Protein kinase C (PKC)epsilon, a transforming oncogene, has a role in the protection of cardiomyocytes and neurons from hypoxia-induced damage while, it can also modulate the susceptibility of tumor cells to TRAIL-induced cell death. Here we demonstrate that hypoxia induces a tumor cell phenotype highly sensitive to the cytotoxic effects of TRAIL. Based on the observation that: i) PKCepsilon expression levels are impaired during hypoxia, ii) the overexpression of PKCepsilon, but not of a kinase-inactive PKCepsilon mutant, is able to revert the hypoxia-induced sensitivity to TRAIL, iii) the down-modulation of PKCepsilon levels by RNA interference, on the contrary, induces the highly TRAIL-sensitive phenotype, iv) the inhibition of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) by specific siRNA blocks both the hypoxia-induced down-modulation of PKCepsilon and the induction of the highly TRAIL-sensitive phenotype; we conclude that the HIF-1alpha upregulation during hypoxia is associated to PKCepsilon down-modulation that likely represents the key molecular event promoting the apoptogenic effects of TRAIL in hypoxic tumor cells.

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

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    Audrey Sermeus

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

  11. Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

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

    2011-01-01

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

  12. Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.

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    Binns-Loveman, Karen M; Kaplowitz, Mark R; Fike, Candice D

    2005-07-01

    Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

  13. Effects of extracellular modulation through hypoxia on the glucose metabolism of human breast cancer stem cells

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    Yustisia, I.; Jusman, S. W. A.; Wanandi, S. I.

    2017-08-01

    Cancer stem cells have been reported to maintain stemness under certain extracellular changes. This study aimed to analyze the effect of extracellular O2 level modulation on the glucose metabolism of human CD24-/CD44+ breast cancer stem cells (BCSCs). The primary BCSCs (CD24-/CD44+ cells) were cultured under hypoxia (1% O2) for 0.5, 4, 6, 24 and 48 hours. After each incubation period, HIF1α, GLUT1 and CA9 expressions, as well as glucose metabolism status, including glucose consumption, lactate production, O2 consumption and extracellular pH (pHe) were analyzed using qRT-PCR, colorimetry, fluorometry, and enzymatic reactions, respectively. Hypoxia caused an increase in HIF1α mRNA expressions and protein levels and shifted the metabolic states to anaerobic glycolysis, as demonstrated by increased glucose consumption and lactate production, as well as decreased O2 consumption and pHe. Furthermore, we demonstrated that GLUT1 and CA9 mRNA expressions simultaneously increased, in line with HIF1α expression. In conclusion, modulation of the extracellular environment of human BCSCs through hypoxia shifedt the metabolic state of BCSCs to anaerobic glycolysis, which might be associated with GLUT1 and CA9 expressions regulated by HIFlα transcription factor.

  14. A Lab Assembled Microcontroller-Based Sensor Module for Continuous Oxygen Measurement in Portable Hypoxia Chambers.

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    Saroj P Mathupala

    Full Text Available Hypoxia-based cell culture experiments are routine and essential components of in vitro cancer research. Most laboratories use low-cost portable modular chambers to achieve hypoxic conditions for cell cultures, where the sealed chambers are purged with a gas mixture of preset O2 concentration. Studies are conducted under the assumption that hypoxia remains unaltered throughout the 48 to 72 hour duration of such experiments. Since these chambers lack any sensor or detection system to monitor gas-phase O2, the cell-based data tend to be non-uniform due to the ad hoc nature of the experimental setup.With the availability of low-cost open-source microcontroller-based electronic project kits, it is now possible for researchers to program these with easy-to-use software, link them to sensors, and place them in basic scientific apparatus to monitor and record experimental parameters. We report here the design and construction of a small-footprint kit for continuous measurement and recording of O2 concentration in modular hypoxia chambers. The low-cost assembly (US$135 consists of an Arduino-based microcontroller, data-logging freeware, and a factory pre-calibrated miniature O2 sensor. A small, intuitive software program was written by the authors to control the data input and output. The basic nature of the kit will enable any student in biology with minimal experience in hobby-electronics to assemble the system and edit the program parameters to suit individual experimental conditions.We show the kit's utility and stability of data output via a series of hypoxia experiments. The studies also demonstrated the critical need to monitor and adjust gas-phase O2 concentration during hypoxia-based experiments to prevent experimental errors or failure due to partial loss of hypoxia. Thus, incorporating the sensor-microcontroller module to a portable hypoxia chamber provides a researcher a capability that was previously available only to labs with access to

  15. A Lab Assembled Microcontroller-Based Sensor Module for Continuous Oxygen Measurement in Portable Hypoxia Chambers.

    Science.gov (United States)

    Mathupala, Saroj P; Kiousis, Sam; Szerlip, Nicholas J

    2016-01-01

    Hypoxia-based cell culture experiments are routine and essential components of in vitro cancer research. Most laboratories use low-cost portable modular chambers to achieve hypoxic conditions for cell cultures, where the sealed chambers are purged with a gas mixture of preset O2 concentration. Studies are conducted under the assumption that hypoxia remains unaltered throughout the 48 to 72 hour duration of such experiments. Since these chambers lack any sensor or detection system to monitor gas-phase O2, the cell-based data tend to be non-uniform due to the ad hoc nature of the experimental setup. With the availability of low-cost open-source microcontroller-based electronic project kits, it is now possible for researchers to program these with easy-to-use software, link them to sensors, and place them in basic scientific apparatus to monitor and record experimental parameters. We report here the design and construction of a small-footprint kit for continuous measurement and recording of O2 concentration in modular hypoxia chambers. The low-cost assembly (US$135) consists of an Arduino-based microcontroller, data-logging freeware, and a factory pre-calibrated miniature O2 sensor. A small, intuitive software program was written by the authors to control the data input and output. The basic nature of the kit will enable any student in biology with minimal experience in hobby-electronics to assemble the system and edit the program parameters to suit individual experimental conditions. We show the kit's utility and stability of data output via a series of hypoxia experiments. The studies also demonstrated the critical need to monitor and adjust gas-phase O2 concentration during hypoxia-based experiments to prevent experimental errors or failure due to partial loss of hypoxia. Thus, incorporating the sensor-microcontroller module to a portable hypoxia chamber provides a researcher a capability that was previously available only to labs with access to sophisticated (and

  16. Modulation of KATP currents in rat ventricular myocytes by hypoxia and a redox reaction

    Institute of Scientific and Technical Information of China (English)

    Xi-sheng YAN; Ji-hua MA; Pei-hua ZHANG

    2009-01-01

    Aim:The present study investigated the possible regulatory mechanisms of redox agents and hypoxia on the K_(ATP) current (I_(KATP)) in acutely isolated rat ventricular myocytes.Methods: Single-channel and whole-cell patch-clamp techniques were used to record the K_(ATP) current (I_(KATP)) in acutely isolated rat ven-tricular myocytes.Results: Oxidized glutathione (GSSG, 1 mmol/L) increased the I_(KATP), while reduced glutathione (GSH, 1 mmol/L) could reverse the increased I_(KATP) during normoxia. To further corroborate the effect of the redox agent on the KATP channel, we employed the redox couple DTT (1 mmol/L)/H_2O_2 (0.3, 0.6, and 1 mmol/L) and repeated the previous processes, which produced results similar to the previous redox couple GSH/GSSG during normoxia. H_2O_2 increased the I_(KATP) in a concentration dependent manner, which was reversed by DTT (1 mmol/L). In addition, our results have shown that 15 min of hypoxia increased the I_(KATP), while GSH (1 mmol/L) could reverse the increased I_(KATP). Furthermore, in order to study the signaling pathways of the I_(KATP) augmented by hypoxia and the redox agent, we applied a protein kinase C(PKC) inhibitor bisindolylmaleimide VI (BIM), a protein kinase G(PKG) inhibitor KT5823, a protein kinase A (PKA) inhibitor H-89, and Ca(2+)/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) inhibitors KN-62 and KN-93. The results indicated that BIM, KT5823, KN-62, and KN-93, but not H-89, inhibited the IKATPaugmented by hypoxia and GSSG; in addition, these results sug-gest that the effects of both GSSG and hypoxia on K_(ATP) channels involve the activation of the PKC, PKG, and CaMK Ⅱ pathways, but not the PKA pathway.Conclusion: The present study provides electrophysiological evidence that hypoxia and the oxidizing reaction are closely related to the modulation of I_(KATP).

  17. ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

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    Melissa M Keenan

    2015-10-01

    Full Text Available In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1 or ATP citrate lyase (ACLY protected cancer cells from hypoxia-induced apoptosis. Additionally, the loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased under hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4, likely via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that the ACC1/ACLY-α-ketoglutarate-ETV4 axis is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.

  18. Ets-1 as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells.

    Science.gov (United States)

    Qiao, N; Xu, C; Zhu, Y-X; Cao, Y; Liu, D-C; Han, X

    2015-02-19

    Hypoxia complicates islet isolation for transplantation and may contribute to pancreatic β-cell failure in type 2 diabetes. Pancreatic β-cells are susceptible to hypoxia-induced apoptosis. Severe hypoxic conditions during the immediate post-transplantation period are a main non-immune factor leading to β-cell death and islet graft failure. In this study, we identified the transcription factor Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) as an early response gene against hypoxia-induced apoptosis in pancreatic β-cells. Hypoxia regulates Ets-1 at multiple levels according to the degree of β-cell oxygen deprivation. Moderate hypoxia promotes Ets-1 gene transcription, whereas severe hypoxia promotes its transactivation activity, as well as its ubiquitin-proteasome mediated degradation. This degradation causes a relative insufficiency of Ets-1 activity, and limits the transactivation effect of Ets-1 on downstream hypoxic-inducible genes and its anti-apoptotic function. Overexpression of ectopic Ets-1 in MIN6 and INS-1 cells protects them from severe hypoxia-induced apoptosis in a mitochondria-dependent manner, confirming that a sufficient amount of Ets-1 activity is critical for protection of pancreatic β-cells against hypoxic injury. Targeting Ets-1 expression may be a useful strategy for islet graft protection during the immediate post-transplantation period.

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

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

    2014-08-30

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

  20. Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1alpha.

    Science.gov (United States)

    Rho, Jin Kyung; Choi, Yun Jung; Lee, Jin Kyung; Ryoo, Baek-Yeol; Na, Im Ii; Yang, Sung Hyun; Kim, Cheol Hyeon; Yoo, Young Do; Lee, Jae Cheol

    2009-03-01

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1alpha expression. In our data, treatment of gefitinib suppressed induced HIF-1alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1alpha mRNA. The effect of gefitinib on down-regulation of HIF-1alpha was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1alpha expression. In addition, the suppression of HIF-1alpha using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.

  1. Early life exposure to chronic intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during adulthood.

    LENUS (Irish Health Repository)

    McDonald, Fiona B

    2016-03-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and\\/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  2. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle During Adulthood

    Directory of Open Access Journals (Sweden)

    Fiona B Mcdonald

    2016-03-01

    Full Text Available Intermittent hypoxia is a feature of apnea of prematurity, chronic lung disease and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH during postnatal development (pCIH causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 hours of delivery, pups and their respective dams were exposed to CIH: 90s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 hrs per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH, where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  3. Dynamic FDG PET for assessing early effects of cerebral hypoxia and resuscitation in new-born pigs

    Energy Technology Data Exchange (ETDEWEB)

    Lange, Charlotte de [Oslo University Hospital, Rikshospitalet, Department of Paediatric Research, P.O. Box 4950, Oslo (Norway); Oslo University Hospital, Rikshospitalet, Department of Radiology and Nuclear Medicine, P.O. Box 4950, Oslo (Norway); Malinen, Eirik [Oslo University Hospital, Department of Medical Physics, P.O. Box 4953, Oslo (Norway); University of Oslo, Department of Physics, P.O. Box 1048, Oslo (Norway); Qu, Hong [University of Oslo, Centre for Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, P.O. Box 1105, Oslo (Norway); Johnsrud, Kjersti [Oslo University Hospital, Rikshospitalet, Department of Radiology and Nuclear Medicine, P.O. Box 4950, Oslo (Norway); Skretting, Arne [Oslo University Hospital, The Intervention Centre, P.O. Box 4950, Oslo (Norway); Saugstad, Ola Didrik [Oslo University Hospital, Rikshospitalet, Department of Paediatric Research, P.O. Box 4950, Oslo (Norway); University of Oslo, Department of Medicine, P.O. Box 1078, Oslo (Norway); Munkeby, Berit H. [Oslo University Hospital, Rikshospitalet, Department of Paediatric Research, P.O. Box 4950, Oslo (Norway)

    2012-05-15

    Changes in cerebral glucose metabolism may be an early prognostic indicator of perinatal hypoxic-ischaemic injury. In this study dynamic {sup 18}F-FDG PET was used to evaluate cerebral glucose metabolism in piglets after global perinatal hypoxia and the impact of the resuscitation strategy using room air or hyperoxia. New-born piglets (n = 16) underwent 60 min of global hypoxia followed by 30 min of resuscitation with a fraction of inspired oxygen (FiO{sub 2}) of 0.21 or 1.0. Dynamic FDG PET, using a microPET system, was performed at baseline and repeated at the end of resuscitation under stabilized haemodynamic conditions. MRI at 3 T was performed for anatomic correlation. Global and regional cerebral metabolic rates of glucose (CMR{sub gl}) were assessed by Patlak analysis for the two time-points and resuscitation groups. Global hypoxia was found to cause an immediate decrease in cerebral glucose metabolism from a baseline level (mean {+-} SD) of 21.2 {+-} 7.9 to 12.6 {+-} 4.7 {mu}mol/min/100 g (p <0.01). The basal ganglia, cerebellum and cortex showed the greatest decrease in CMR{sub gl} but no significant differences in global or regional CMR{sub gl} between the resuscitation groups were found. Dynamic FDG PET detected decreased cerebral glucose metabolism early after perinatal hypoxia in piglets. The decrease in CMR{sub gl} may indicate early changes of mild cerebral hypoxia-ischaemia. No significant effect of hyperoxic resuscitation on the degree of hypometabolism was found in this early phase after hypoxia. Cerebral FDG PET can provide new insights into mechanisms of perinatal hypoxic-ischaemic injury where early detection plays an important role in instituting therapy. (orig.)

  4. Multimodal hypoxia imaging and intensity modulated radiation therapy for unresectable non-small-cell lung cancer: the HIL trial

    Directory of Open Access Journals (Sweden)

    Askoxylakis Vasileios

    2012-09-01

    Full Text Available Abstract Background Radiotherapy, preferably combined with chemotherapy, is the treatment standard for locally advanced, unresectable non-small cell lung cancer (NSCLC. The tumor response to different therapy protocols is variable, with hypoxia known to be a major factor that negatively influences treatment effectiveness. Visualisation of tumor hypoxia prior to the use of modern radiation therapy strategies, such as intensity modulated radiation therapy (IMRT, might allow optimized dose applications to the target volume, leading to improvement of therapy outcome. 18 F-fluoromisonidazole dynamic positron emission tomography and computed tomography (18 F-FMISO dPET-CT and functional magnetic resonance imaging (functional MRI are attractive options for imaging tumor hypoxia. Methods/design The HIL trial is a single centre study combining multimodal hypoxia imaging with 18 F-FMISO dPET-CT and functional MRI, with intensity modulated radiation therapy (IMRT in patients with inoperable stage III NSCLC. 15 patients will be recruited in the study. All patients undergo initial FDG PET-CT and serial 18 F-FMISO dPET-CT and functional MRI before treatment, at week 5 of radiotherapy and 6 weeks post treatment. Radiation therapy is performed as inversely planned IMRT based on 4D-CT. Discussion Primary objectives of the trial are to characterize the correlation of 18 F-FMISO dPET-CT and functional MRI for tumor hypoxia imaging in NSCLC and evaluate possible effects of radiation therapy on tumor re-oxygenation. Further objectives include the generation of data regarding the prognostic value of 18 F-FMISO dPET-CT and functional MRI for locoregional control, progression free survival and overall survival of NSCLC treated with IMRT, which will form the basis for larger clinical trials focusing on possible interactions between tumor oxygenation and radiotherapy outcome. Trial registration The ClinicalTrials.gov protocol ID is NCT01617980

  5. Analysis of the early adaptive response of endothelial cells to hypoxia via a long serial analysis of gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Guang-Ping; Su, Yong-Yue; Chen, Jian; Yang, Zong-Cheng [State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Liu, You-Sheng [Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Luo, Xiang-Dong, E-mail: luoxd2005@163.com [State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China)

    2009-07-10

    Activation of endothelial cells in humans is an early event in the response to hypoxia that may contribute to the endothelium's endogenous capacity to reduce tissue injury. To better understand the mechanism underlying this process, we utilized Long Serial Analysis of Gene Expression to study the transcriptome of human vein umbilical endothelial cells (EA.hy926) shortly after the induction of hypoxia. Of over 13,000 genes detected in each pool, 112 showed obvious differences in expression. Metabolic processes such as protein biosynthesis and proteolysis, aminoglycan metabolism, ribonucleotide biosynthesis, adenosine salvage, and lipid metabolism were reinforced. Pro-proliferation and pro-apoptotic states suggest the co-existence of pro- and anti-injury forces in endothelium shortly after the induction of hypoxia. Other adaptive responses include reinforced angiogenesis and vasodilation. Additionally, gene transcription in the endothelium shortly after the induction of hypoxia was regulated independently of HIF-1{alpha}. Our efforts to elucidate the adaptive response at an early post-hypoxia stage should contribute to further investigation of the protective processes that occur in the endothelium and has potential clinical implications.

  6. The reoxygenation of hypoxia and the reduction of glucose metabolism in head and neck cancer by fractionated radiotherapy with intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Okamoto, Shozo; Shiga, Tohru; Watanabe, Shiro; Hirata, Kenji; Magota, Keiichi; Kasai, Katsuhiko; Tamaki, Nagara [Hokkaido University Graduate School of Medicine, Department of Nuclear Medicine, Hokkaido (Japan); Yasuda, Koichi; Onimaru, Rikiya; Tuchiya, Kazuhiko; Shirato, Hiroki [Hokkaido University Graduate School of Medicine, Department of Radiology, Hokkaido (Japan); Nishijima, Ken-ichi; Kuge, Yuji [Hokkaido University, Central Institute of Isotope Science, Hokkaido (Japan)

    2016-11-15

    The purpose of this study was to prospectively investigate reoxygenation in the early phase of fractionated radiotherapy and serial changes of tumoricidal effects associated with intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer (HNC) using F-18 fluoromisonidazole (FMISO) PET and F-18 fluorodeoxyglucose (FDG) PET. Patients with untreated HNC underwent FMISO-PET and FDG-PET studies prospectively. A PET evaluation was conducted before each IMRT (Pre-IMRT), during IMRT (at 30 Gy/15 fr) (Inter-IMRT), and after completion of IMRT (70 Gy/35 fr) (Post-IMRT). FMISO-PET images were scanned by a PET/CT scanner at 4 h after the FMISO injection. We quantitatively analyzed the FMISO-PET images of the primary lesion using the maximum standardized uptake (SUVmax) and tumor-to-muscle ratio (TMR). The hypoxic volume (HV) was calculated as an index of tumor hypoxia, and was defined as the volume when the TMR was ≥ 1.25. Each FDG-PET scan was started 1 h after injection. The SUVmax and metabolic tumor volume (MTV) values obtained by FDG-PET were analyzed. Twenty patients finished the complete PET study protocol. At Pre-IMRT, 19 patients had tumor hypoxia in the primary tumor. In ten patients, the tumor hypoxia disappeared at Inter-IMRT. Another seven patients showed the disappearance of tumor hypoxia at Post-IMRT. Two patients showed tumor hypoxia at Post-IMRT. The FMISO-PET results showed that the reduction rates of both SUVmax and TMR from Pre-IMRT to Inter-IMRT were significantly higher than the corresponding reductions from Inter-IMRT to Post-IMRT (SUVmax: 27 % vs. 10 %, p = 0.025; TMR: 26 % vs. 12 %, p = 0.048). The reduction rate of SUVmax in FDG-PET from Pre-IMRT to Inter-IMRT was similar to that from Inter-IMRT to Post-IMRT (47 % vs. 48 %, p = 0.778). The reduction rate of the HV in FMISO-PET from Pre-IMRT to Inter-IMRT tended to be larger than that from Inter-IMRT to Post-IMRT (63 % vs. 40 %, p = 0.490). Conversely, the reduction rate of

  7. 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.

  8. Novel Peptide for Attenuation of Hypoxia-Induced Pulmonary Hypertension via Modulation of Nitric Oxide Release and Phosphodiesterase -5 Activity

    Science.gov (United States)

    Hu, Hanbo; Zharikov, Sergey; Patel, Jawaharlal M.

    2012-01-01

    Pulmonary vascular endothelial nitric oxide (NO) synthase (eNOS)-derived NO is the major stimulant of cyclic guanosine 5’ monophosphate (cGMP) production and NO/cGMP-dependent vasorelaxation in the pulmonary circulation. We recently synthesized multiple peptides and reported that an eleven amino acid (SSWRRKRKESS) peptide (P1) but not scrambled P1 stimulated the catalytic activity but not expression of eNOS and causes NO/cGMP-dependent sustained vasorelaxation in isolated pulmonary artery (PA) segments and in lung perfusion models. Since cGMP levels can also be elevated by inhibition of phosphodiesterase type 5 (PDE-5), this study was designed to test the hypothesis that P1-mediated vesorelaxation is due to its unique dual action as NO-releasing PDE-5 inhibitor in the pulmonary circulation. Treatment of porcine PA endothelial cells (PAEC) with P1 caused time-dependent increase in intracellular NO release and inhibition of the catalytic activity of cGMP-specific PDE-5 but not PDE-5 protein expression leading to increased levels of cGMP. Acute hypoxia-induced PA vasoconstriction ex-vivo and continuous telemetry monitoring of hypoxia (10% oxygen)-induced elevated PA pressure in freely moving rats were significantly restored by administration of P1. Chronic hypoxia (10% oxygen for 4 weeks)-induced alterations in PA perfusion pressure, right ventricular hypertrophy, and vascular remodeling were attenuated by P1 treatment. These results demonstrate the potential therapeutic effects of P1 to prevent and/or arrest the progression of hypoxia-induced PAH via NO/cGMP-dependent modulation of hemodynamic and vascular remodeling in the pulmonary circulation. PMID:22465621

  9. Acute Cobalt-Induced Lung Injury and the Role of Hypoxia-Inducible Factor 1α in Modulating Inflammation

    Science.gov (United States)

    Saini, Yogesh; Greenwood, Krista K.; Merrill, Christian; Kim, Kyung Y.; Patial, Sonika; Parameswaran, Narayanan; Harkema, Jack R.; LaPres, John J.

    2010-01-01

    Air pollution is a critical factor in the development and exacerbation of pulmonary diseases. Ozone, automobile exhaust, cigarette smoke, and metallic dust are among the potentially harmful pollution components that are linked to disease progression. Transition metals, such as cobalt, have been identified at significant levels in air pollution. Cobalt exerts numerous biological effects, including mimicking hypoxia. Similar to hypoxia, cobalt exposure results in the stabilization of hypoxia-inducible factors (HIFs), a family of proteins that regulate the cellular response to oxygen deficit. HIFs also play an important role in innate immunity and inflammatory processes. To characterize the role of HIF1α, the most ubiquitously expressed HIF, in the early events during cobalt-induced lung inflammation, an inducible lung-specific HIF1α deletion model was employed. Control mice showed classical signs of metal-induced injury following cobalt exposure, including neutrophilic infiltration and induction of Th1 cytokines. In contrast, HIF1α-deficient mice exhibited pronounced eosinophil counts in bronchoalveolar lavage fluid and lung tissue complemented with Th2 cytokine induction. The timing of these results suggests that the loss of epithelial-derived HIF1α alters the lung's innate immune response and biases the tissue toward a Th2-mediated inflammation. PMID:20511350

  10. Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.

    Science.gov (United States)

    Thomas, Joanna L; Pham, Hai; Li, Ying; Hall, Elanore; Perkins, Guy A; Ali, Sameh S; Patel, Hemal H; Singh, Prabhleen

    2017-08-01

    The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.

  11. A numerical analysis of biogeochemical controls with physical modulation on hypoxia during summer in the Pearl River estuary

    Science.gov (United States)

    Wang, Bin; Hu, Jiatang; Li, Shiyu; Liu, Dehong

    2017-06-01

    A three-dimensional (3-D) physical-biogeochemical coupled model was applied to explore the mechanisms controlling the dissolved oxygen (DO) dynamics and bottom hypoxia during summer in the Pearl River estuary (PRE). By using the numerical oxygen tracers, we proposed a new method (namely the physical modulation method) to quantify the contributions of boundary conditions and each source and sink process occurring in local and adjacent waters to the DO conditions. A mass balance analysis of DO based on the physical modulation method indicated that the DO conditions at the bottom layer were mainly controlled by the source and sink processes, among which the sediment oxygen demand (SOD) at the water-sediment interface and the re-aeration at the air-sea interface were the two primary processes determining the spatial extent and duration of bottom hypoxia in the PRE. The SOD could cause a significant decrease in the bottom DO concentrations (averaged over July-August 2006) by over 4 mg L-1 on the shelf off the Modaomen sub-estuary, leading to the formation of a high-frequency zone of hypoxia (HFZ). However, the hypoxia that occurred in the HFZ was intermittent and distributed in a small area due to the combined effects of re-aeration and photosynthesis, which behaved as sources for DO and offset a portion of the DO consumed by SOD. The bottom DO concentrations to the west of the lower Lingdingyang Bay (i.e. the western shoal near Qi'ao Island) were also largely affected by high SOD, but there was no hypoxia occurring there because of the influence of re-aeration. Specifically, re-aeration could lead to an increase in the bottom DO concentrations by ˜ 4.8 mg L-1 to the west of the lower Lingdingyang Bay. The re-aeration led to a strong vertical DO gradient between the surface and the lower layers. As a result, the majority (˜ 89 %) of DO supplemented by re-aeration was transported to the lower layers through vertical diffusion and ˜ 28 % reached the bottom eventually

  12. Substance P Differentially Modulates Firing Rate of Solitary Complex (SC) Neurons from Control and Chronic Hypoxia-Adapted Adult Rats

    Science.gov (United States)

    Nichols, Nicole L.; Powell, Frank L.; Dean, Jay B.; Putnam, Robert W.

    2014-01-01

    NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H+-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats. PMID:24516602

  13. Substance P differentially modulates firing rate of solitary complex (SC neurons from control and chronic hypoxia-adapted adult rats.

    Directory of Open Access Journals (Sweden)

    Nicole L Nichols

    Full Text Available NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H(+-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS. Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus neurons from control and chronic hypoxia-adapted (CHx adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats.

  14. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.

    Science.gov (United States)

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

    2012-02-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription. ©2011 AACR.

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

    Science.gov (United States)

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

    2012-01-01

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

  16. Withanolide A Prevents Neurodegeneration by Modulating Hippocampal Glutathione Biosynthesis during Hypoxia

    Science.gov (United States)

    Baitharu, Iswar; Jain, Vishal; Deep, Satya Narayan; Shroff, Sabita; Sahu, Jayanta Kumar; Naik, Pradeep Kumar; Ilavazhagan, Govindasamy

    2014-01-01

    Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner

  17. Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression

    Directory of Open Access Journals (Sweden)

    Currie Margaret J

    2006-12-01

    Full Text Available Abstract Background A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies. Combretastatin A-4 phosphate (CA-4-P is a tubulin-depolymerising agent in Phase II clinical trials as a vascular disrupting agent. Not much is known of the molecular effect of CA-4-P under tumour conditions. The tumour microenvironment differs markedly from that in normal tissue, specifically with respect to oxygenation (hypoxia. Gene regulation under tumour conditions is governed by hypoxia inducible factor 1 (HIF-1, controlling angiogenic and metastatic pathways. Methods We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro. Results CA-4-P treatment under hypoxia tended to reduce HIF-1 accumulation in a concentration-dependent manner, an effect which was more prominent in endothelial cells than in cancer cell lines. Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions in vitro. At these concentrations of CA-4-P under aerobic conditions, nuclear factor κB was activated via the small GTPase RhoA, and expression of the HIF-1 downstream angiogenic effector gene, vascular endothelial growth factor (VEGF-A, was increased. Conclusion Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.

  18. Dry Needling at Myofascial Trigger Spots of Rabbit Skeletal Muscles Modulates the Biochemicals Associated with Pain, Inflammation, and Hypoxia

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    Yueh-Ling Hsieh

    2012-01-01

    Full Text Available Background and Purpose. Dry needling is an effective therapy for the treatment of pain associated with myofascial trigger point (MTrP. However, the biochemical effects of dry needling that are associated with pain, inflammation, and hypoxia are unclear. This study investigated the activities of β-endorphin, substance P, TNF-α, COX-2, HIF-1α, iNOS, and VEGF after different dosages of dry needling at the myofascial trigger spots (MTrSs of a skeletal muscle in rabbit. Materials and Methods. Dry needling was performed either with one dosage (1D or five dosages (5D into the biceps femoris with MTrSs in New Zealand rabbits. Biceps femoris, serum, and dorsal root ganglion (DRG were sampled immediately and 5 d after dry needling for β-endorphin, substance P, TNF-α, COX-2, HIF-1α, iNOS, and VEGF immunoassays. Results. The 1D treatment enhanced the β-endorphin levels in the biceps femoris and serum and reduced substance P in the biceps femoris and DRG. The 5D treatment reversed these effects and was accompanied by increase of TNF-α, COX-2, HIF-1α, iNOS, and VEGF production in the biceps femoris. Moreover, the higher levels of these biochemicals were still maintained 5 d after treatment. Conclusion. Dry needling at the MTrSs modulates various biochemicals associated with pain, inflammation, and hypoxia in a dose-dependent manner.

  19. Dry Needling at Myofascial Trigger Spots of Rabbit Skeletal Muscles Modulates the Biochemicals Associated with Pain, Inflammation, and Hypoxia

    Science.gov (United States)

    Hsieh, Yueh-Ling; Yang, Shun-An; Yang, Chen-Chia; Chou, Li-Wei

    2012-01-01

    Background and Purpose. Dry needling is an effective therapy for the treatment of pain associated with myofascial trigger point (MTrP). However, the biochemical effects of dry needling that are associated with pain, inflammation, and hypoxia are unclear. This study investigated the activities of β-endorphin, substance P, TNF-α, COX-2, HIF-1α, iNOS, and VEGF after different dosages of dry needling at the myofascial trigger spots (MTrSs) of a skeletal muscle in rabbit. Materials and Methods. Dry needling was performed either with one dosage (1D) or five dosages (5D) into the biceps femoris with MTrSs in New Zealand rabbits. Biceps femoris, serum, and dorsal root ganglion (DRG) were sampled immediately and 5 d after dry needling for β-endorphin, substance P, TNF-α, COX-2, HIF-1α, iNOS, and VEGF immunoassays. Results. The 1D treatment enhanced the β-endorphin levels in the biceps femoris and serum and reduced substance P in the biceps femoris and DRG. The 5D treatment reversed these effects and was accompanied by increase of TNF-α, COX-2, HIF-1α, iNOS, and VEGF production in the biceps femoris. Moreover, the higher levels of these biochemicals were still maintained 5 d after treatment. Conclusion. Dry needling at the MTrSs modulates various biochemicals associated with pain, inflammation, and hypoxia in a dose-dependent manner. PMID:23346198

  20. Heme oxygenase isoforms differ in their subcellular trafficking during hypoxia and are differentially modulated by cytochrome P450 reductase.

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    Monika Linnenbaum

    Full Text Available Heme oxygenase (HO degrades heme in concert with NADPH cytochrome P450 reductase (CPR which donates electrons to the reaction. Earlier studies reveal the importance of the hydrophobic carboxy-terminus of HO-1 for anchorage to the endoplasmic reticulum (ER which facilitates the interaction with CPR. In addition, HO-1 has been shown to undergo regulated intramembrane proteolysis of the carboxy-terminus during hypoxia and subsequent translocation to the nucleus. Translocated nuclear HO-1 was demonstrated to alter binding of transcription factors and to alter gene expression. Little is known about the homologous membrane anchor of the HO-2 isoform. The current work is the first systematic analysis in a eukaryotic system that demonstrates the crucial role of the membrane anchor of HO-2 for localization at the endoplasmic reticulum, oligomerization and interaction with CPR. We show that although the carboxy-terminal deletion mutant of HO-2 is found in the nucleus, translocation of HO-2 to the nucleus does not occur under conditions of hypoxia. Thus, we demonstrate that proteolytic regulation and nuclear translocation under hypoxic conditions is specific for HO-1. In addition we show for the first time that CPR prevents this translocation and promotes oligomerization of HO-1. Based on these findings, CPR may modulate gene expression via the amount of nuclear HO-1. This is of particular relevance as CPR is a highly polymorphic gene and deficiency syndromes of CPR have been described in humans.

  1. Anaemia adjusts the aerobic physiology of snapper (Pagrus auratus) and modulates hypoxia avoidance behaviour during oxygen choice presentations.

    Science.gov (United States)

    Cook, Denham G; Wells, Rufus M G; Herbert, Neill A

    2011-09-01

    The effect of altered oxygen transport potential on behavioural responses to environmental hypoxia was tested experimentally in snapper, Pagrus auratus, treated with a haemolytic agent (phenylhydrazine) or a sham protocol. Standard metabolic rate was not different between anaemic and normocythaemic snapper (Hct=6.7 and 25.7 g dl(-1), respectively), whereas maximum metabolic rate, and hence aerobic scope (AS), was consistently reduced in anaemic groups at all levels of water P(O(2)) investigated (Pspeed. Despite differences in physiological and behavioural parameters, both groups avoided low P(O(2)) just below their P(crit), indicating that avoidance was triggered consistently when AS limits were reached and anaerobic metabolism was unavoidable. This was confirmed by high levels of plasma lactate in both treatments at the point of avoidance. This is the first experimental demonstration of avoidance behaviour being modulated by internal physiological state. From an ecological perspective, fish with disturbed oxygen delivery potential arising from anaemia, pollution or stress are likely to avoid environmental hypoxia at a higher P(O(2)) than normal fish.

  2. MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3*S⃞

    Science.gov (United States)

    Fasanaro, Pasquale; D'Alessandra, Yuri; Di Stefano, Valeria; Melchionna, Roberta; Romani, Sveva; Pompilio, Giulio; Capogrossi, Maurizio C.; Martelli, Fabio

    2008-01-01

    MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation. PMID:18417479

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

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    Mahendran Botlagunta

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

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

    Science.gov (United States)

    Botlagunta, Mahendran; Krishnamachary, Balaji; Vesuna, Farhad; Winnard, Paul T; Bol, Guus M; Patel, Arvind H; Raman, Venu

    2011-03-23

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

  5. Early Cellular Responses of Purine Nucleoside-mediated Protection of Hypoxia-induced Injuries of Neuronal PC12 Cells

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    Bettina Tomaselli

    2005-01-01

    Full Text Available Hypoxia in brain may lead to cell death by apoptosis and necrosis. In parallel adenosine, a powerful endogenous neuroprotectant is formed. We wanted to investigate the effect of adenosine and its purine nucleoside relatives, inosine and guanosine on early cellular responses to hypoxia. O2-sensitive neuronal PC12-cells were subjected to chemical hypoxia induced with rotenone, an inhibitor of mitochondrial complex I. Loss of viability after hypoxic insult was impressively rescued by adenosine, guanosine and inosine. PC12-cells mainly express the A2A adenosine receptor. Its inhibition with a specific antagonist (CSC induced cell death of PC12-cells, which could be salvaged by adenosine but not with guanosine or inosine. We have previously demonstrated the important role of mitogen activated protein kinases 1/2 (p42/44 MAPK in purine-mediated rescue. In this study we were interested in the involvement of protein kinases whose activities mediate these processes, including protein kinase A (PKA, phosphoinositide 3-kinase (PI3-K and protein kinase C-related kinases (PRK 1/2. Pharmacological inhibition of PKA and PI3-K increased hypoxia-induced toxicity and likewise also affected the rescue by purine nucleosides. Nerve growth factor (NGF and purine nucleosides induced an activation of PRK 1/2, which to our knowledge indicates for the first time that these kinases are potentially involved in purine nucleoside-mediated rescue of hypoxic neuronal cells. Results suggest that A2A receptor expressing cells are mainly dependent on the purine nucleoside adenosine for their rescue after hypoxic insult. In addition to PKA, PI3-K is an important effector molecule in A2A-mediated signaling and for the rescue of PC12-cells after hypoxic insult.

  6. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.

    Science.gov (United States)

    Betof, Allison S; Lascola, Christopher D; Weitzel, Douglas; Landon, Chelsea; Scarbrough, Peter M; Devi, Gayathri R; Palmer, Gregory; Jones, Lee W; Dewhirst, Mark W

    2015-05-01

    Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer. © The Author 2015. Published by Oxford University Press.

  7. Spatial attention modulates early face processing.

    Science.gov (United States)

    Feng, Wenfeng; Martinez, Antigona; Pitts, Michael; Luo, Yue-Jia; Hillyard, Steven A

    2012-12-01

    It is widely reported that inverting a face dramatically affects its recognition. Previous studies have shown that face inversion increases the amplitude and delays the latency of the face-specific N170 component of the event-related potential (ERP) and also enhances the amplitude of the occipital P1 component (latency 100-132 ms). The present study investigates whether these effects of face inversion can be modulated by visual spatial attention. Participants viewed two streams of visual stimuli, one to the left and one to the right of fixation. One stream consisted of a sequence of alphanumeric characters at 6.67 Hz, and the other stream consisted of a series of upright and inverted images of faces and houses presented in randomized order. The participants' task was to attend selectively to one or the other of the streams (during different blocks) in order to detect infrequent target stimuli. ERPs elicited by inverted faces showed larger P1 amplitudes compared to upright faces, but only when the faces were attended. In contrast, the N170 amplitude was larger to inverted than to upright faces only when the faces were not attended. The N170 peak latency was delayed to inverted faces regardless of attention condition. These inversion effects were face specific, as similar effects were absent for houses. These results suggest that early stages of face-specific processing can be enhanced by attention, but when faces are not attended the onset of face-specific processing is delayed until the latency range of the N170.

  8. PLC-β2 is modulated by low oxygen availability in breast tumor cells and plays a phenotype dependent role in their hypoxia-related malignant potential.

    Science.gov (United States)

    Brugnoli, Federica; Grassilli, Silvia; Al-Qassab, Yasamin; Capitani, Silvano; Bertagnolo, Valeria

    2016-12-01

    Limited oxygen availability plays a critical role in the malignant progression of breast cancer by orchestrating a complex modulation of the gene transcription largely dependent on the tumor phenotype. Invasive breast tumors belonging to different molecular subtypes are characterized by over-expression of PLC-β2, whose amount positively correlates with the malignant evolution of breast neoplasia and supports the invasive potential of breast tumor cells. Here we report that hypoxia modulates the expression of PLC-β2 in breast tumor cells in a phenotype-related manner, since a decrease of the protein was observed in the BT-474 and MCF7 cell lines while an increase was revealed in MDA-MB-231 cells as a consequence of low oxygen availability. Under hypoxia, the down-modulation of PLC-β2 was mainly correlated with the decrease of the EMT marker E-cadherin in the BT-474 cells and with the up-regulation of the stem cell marker CD133 in MCF7 cells. The increase of PLC-β2 induced by low oxygen in MDA-MB-231 cells supports the hypoxia-related reorganization of actin cytoskeleton and sustains invasion capability. In all examined cell lines, but with an opposite role in the ER-positive and ER-negative cells, PLC-β2 was involved in the hypoxia-induced increase of HIF-1α, known to affect both EMT and CD133 expression. Our data include PLC-β2 in the complex and interconnected signaling pathways induced by low oxygen availability in breast tumor cells and suggest that the forced modulation of PLC-β2 programmed on the basis of tumor phenotype may prevent the malignant progression of breast neoplasia as a consequence of intra-tumoral hypoxia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Hypoxia and brain development

    NARCIS (Netherlands)

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

    1996-01-01

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

  10. Haemoglobin modulates NO emission and hyponasty under hypoxia-related stress in Arabidopsis thaliana

    DEFF Research Database (Denmark)

    Hebelstrup, Kim; van Zanten, Martijn; Mandon, Julien;

    2012-01-01

    Nitric oxide (NO) and ethylene are signalling molecules that are synthesized in response to oxygen depletion. Non-symbiotic plant haemoglobins (Hbs) have been demonstrated to act in roots under oxygen depletion to scavenge NO. Using Arabidopsis thaliana plants, the online emission of NO or ethylene...... represented a major loss of nitrogen equivalent to 0.2mM nitrate per 24h under hypoxic conditions. Hb gene expression was greatly enhanced in flooded roots, suggesting induction by reduced oxygen diffusion. The function could be to limit loss of nitrogen under NO emission. NO reacts with thiols to form S......-nitrosylated compounds, and it is demonstrated that hypoxia substantially increased the content of S-nitrosylated compounds. A parallel up-regulation of Hb gene expression in the normoxic shoots of the flooded plants may reflect signal transmission from root to shoot via ethylene and a role for Hb in the shoots. Hb gene...

  11. Graded hypoxia modulates the invasive potential of HT1080 fibrosarcoma and MDA MB231 carcinoma cells.

    Science.gov (United States)

    Subarsky, Patrick; Hill, Richard P

    2008-01-01

    Spatial and temporal oxygen heterogeneity exists in most solid tumour microenvironments due to an inadequate vascular network supplying a dense population of tumour cells. An imbalance between oxygen supply and demand leads to hypoxia within a significant proportion of a tumour, which has been correlated to the likelihood of metastatic dissemination in both rodent tumour models and human patients. Experimentally, it has been demonstrated that near-anoxic in vitro exposure results in transiently increased metastatic potential in some tumour cell lines. The purpose of this study was to examine the effect of graded low oxygen conditions on the invasive phenotype of human tumour cells using an in vitro model of basement membrane invasion, in which we measured oxygen availability directly at the invasion surface of the transwell chamber. Our results show a relationship between culture vessel geometry and time to achieve hypoxia which may affect the interpretation of low oxygen experiments. We exposed the human tumour cell lines, HT1080 and MDA MB231, to graded normobaric oxygen (5% O(2)-0.2% O(2)) either during or prior to in vitro basement membrane invasion to simulate conditions of intravasation and extravasation. A secondary aim was to investigate the potential regulation of matrix metalloproteinase activity by oxygen availability. We identified significant reductions in invasive ability under low oxygen conditions for the HT1080 cell line and an increase in invasion at intermediate oxygen conditions for the MDA MB231 cell line. There were differences in the absolute activity of the individual matrix metalloproteinases, MMP-2, -9, -14, between the two cell lines, however there were no significant changes following exposure to hypoxic conditions. This study demonstrates cell line specific effects of graded oxygen levels on invasive potential and suggests that intermediate levels of low oxygen may increase metastatic dissemination.

  12. RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3beta signaling pathways.

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    Linshan Shang

    Full Text Available BACKGROUND: Advanced glycation end-products (AGEs have been implicated in diverse pathological settings including diabetes, inflammation and acute ischemia/reperfusion injury in the heart. AGEs interact with the receptor for AGEs (RAGE and transduce signals through activation of MAPKs and proapoptotic pathways. In the current study, adult cardiomyocytes were studied in an in vitro ischemia/reperfusion (I/R injury model to delineate the molecular mechanisms underlying RAGE-mediated injury due to hypoxia/reoxygenation (H/R. METHODOLOGY/PRINCIPAL FINDINGS: Cardiomyocytes isolated from adult wild-type (WT, homozygous RAGE-null (RKO, and WT mice treated with soluble RAGE (sRAGE were subjected to hypoxia for 30 minutes alone or followed by reoxygenation for 1 hour. In specific experiments, RAGE ligand carboxymethyllysine (CML-AGE (termed "CML" in this manuscript was evaluated in vitro. LDH, a marker of cellular injury, was assayed in the supernatant in the presence or absence of signaling inhibitor-treated cardiomyocytes. Cardiomyocyte levels of heterogeneous AGEs were measured using ELISA. A pronounced increase in RAGE expression along with AGEs was observed in H/R vs. normoxia in WT cardiomyocytes. WT cardiomyocytes after H/R displayed increased LDH release compared to RKO or sRAGE-treated cardiomyocytes. Our results revealed significant increases in phospho-JNK in WT cardiomyocytes after H/R. In contrast, neither RKO nor sRAGE-treated cardiomyocytes exhibited increased phosphorylation of JNK after H/R stress. The impact of RAGE deletion on GSK-3beta phosphorylation in the cardiomyocytes subjected to H/R revealed significantly higher levels of phospho-GSK-3beta/total GSK-3beta in RKO, as well as in sRAGE-treated cardiomyocytes versus WT cardiomyocytes after H/R. Further investigation established a key role for Akt, which functions upstream of GSK-3beta, in modulating H/R injury in adult cardiomyocytes. CONCLUSIONS/SIGNIFICANCE: These data illustrate

  13. Adipose Mesenchymal Stem Cell Secretome Modulated in Hypoxia for Remodeling of Radiation-Induced Salivary Gland Damage.

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    Hye-Young An

    Full Text Available This study was conducted to determine whether a secretome from mesenchymal stem cells (MSC modulated by hypoxic conditions to contain therapeutic factors contributes to salivary gland (SG tissue remodeling and has the potential to improve irradiation (IR-induced salivary hypofunction in a mouse model.Human adipose mesenchymal stem cells (hAdMSC were isolated, expanded, and exposed to hypoxic conditions (O2 < 5%. The hypoxia-conditioned medium was then filtered to a high molecular weight fraction and prepared as a hAdMSC secretome. The hAdMSC secretome was subsequently infused into the tail vein of C3H mice immediately after local IR once a day for seven consecutive days. The control group received equal volume (500 μL of vehicle (PBS only. SG function and structural tissue remodeling by the hAdMSC secretome were investigated. Human parotid epithelial cells (HPEC were obtained, expanded in vitro, and then irradiated and treated with either the hypoxia-conditioned medium or a normoxic control medium. Cell proliferation and IR-induced cell death were examined to determine the mechanism by which the hAdMSC secretome exerted its effects.The conditioned hAdMSC secretome contained high levels of GM-CSF, VEGF, IL-6, and IGF-1. Repeated systemic infusion with the hAdMSC secretome resulted in improved salivation capacity and increased levels of salivary proteins, including amylase and EGF, relative to the PBS group. The microscopic structural integrity of SG was maintained and salivary epithelial (AQP-5, endothelial (CD31, myoepithelial (α-SMA and SG progenitor cells (c-Kit were successfully protected from radiation damage and remodeled. The hAdMSC secretome strongly induced proliferation of HPEC and led to a significant decrease in cell death in vivo and in vitro. Moreover, the anti-apoptotic effects of the hAdMSC secretome were found to be promoted after hypoxia-preconditioning relative to normoxia-cultured hAdMSC secretome.These results show that the

  14. Hypoxia modifies the transcriptome of primary human monocytes: modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene.

    Science.gov (United States)

    Bosco, Maria Carla; Puppo, Maura; Santangelo, Clara; Anfosso, Luca; Pfeffer, Ulrich; Fardin, Paolo; Battaglia, Florinda; Varesio, Luigi

    2006-08-01

    Peripheral blood monocytes migrate to and accumulate in hypoxic areas of inflammatory and tumor lesions. To characterize the molecular bases underlying monocyte functions within a hypoxic microenvironment, we investigated the transcriptional profile induced by hypoxia in primary human monocytes using high-density oligonucleotide microarrays. Profound changes in the gene expression pattern were detected following 16 h exposure to 1% O(2), with 536 and 677 sequences showing at least a 1.5-fold increase and decrease, respectively. Validation of this analysis was provided by quantitative RT-PCR confirmation of expression differences of selected genes. Among modulated genes, 74 were known hypoxia-responsive genes, whereas the majority were new genes whose responsiveness to hypoxia had not been previously described. The hypoxic transcriptome was characterized by the modulation of a significant cluster of genes with immunological relevance. These included scavenger receptors (CD163, STAB1, C1qR1, MSR1, MARCO, TLR7), immunoregulatory, costimulatory, and adhesion molecules (CD32, CD64, CD69, CD89, CMRF-35H, ITGB5, LAIR1, LIR9), chemokines/cytokines and receptors (CCL23, CCL15, CCL8, CCR1, CCR2, RDC1, IL-23A, IL-6ST). Furthermore, we provided conclusive evidence of hypoxic induction of CCL20, a chemoattractant for immature dendritic cells, activated/memory T lymphocytes, and naive B cells. CCL20 mRNA up-regulation was paralleled by increased protein expression and secretion. This study represents the first transcriptome analysis of hypoxic primary human monocytes, which provides novel insights into monocyte functional behavior within ischemic/hypoxic tissues. CCL20 up-regulation by hypoxia may constitute an important mechanism to promote recruitment of specific leukocyte subsets at pathological sites and may have implications for the pathogenesis of chronic inflammatory diseases.

  15. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

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    Justin Wang

    Full Text Available Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min. Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute

  16. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

    Science.gov (United States)

    Wang, Justin; Wu, Chiping; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-01-01

    Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging

  17. Hypoxia and acidification have additive and synergistic negative effects on the growth, survival, and metamorphosis of early life stage bivalves.

    Directory of Open Access Journals (Sweden)

    Christopher J Gobler

    Full Text Available Low oxygen zones in coastal and open ocean ecosystems have expanded in recent decades, a trend that will accelerate with climatic warming. There is growing recognition that low oxygen regions of the ocean are also acidified, a condition that will intensify with rising levels of atmospheric CO2. Presently, however, the concurrent effects of low oxygen and acidification on marine organisms are largely unknown, as most prior studies of marine hypoxia have not considered pH levels. We experimentally assessed the consequences of hypoxic and acidified water for early life stage bivalves (bay scallops, Argopecten irradians, and hard clams, Mercenaria mercenaria, marine organisms of significant economic and ecological value and sensitive to climate change. In larval scallops, experimental and naturally-occurring acidification (pH, total scale  = 7.4-7.6 reduced survivorship (by >50%, low oxygen (30-50 µM inhibited growth and metamorphosis (by >50%, and the two stressors combined produced additively negative outcomes. In early life stage clams, however, hypoxic waters led to 30% higher mortality, while acidified waters significantly reduced growth (by 60%. Later stage clams were resistant to hypoxia or acidification separately but experienced significantly (40% reduced growth rates when exposed to both conditions simultaneously. Collectively, these findings demonstrate that the consequences of low oxygen and acidification for early life stage bivalves, and likely other marine organisms, are more severe than would be predicted by either individual stressor and thus must be considered together when assessing how ocean animals respond to these conditions both today and under future climate change scenarios.

  18. Hypoxia-Induced miR-210 Modulates Tissue Response to Acute Peripheral Ischemia

    Science.gov (United States)

    Zaccagnini, Germana; Maimone, Biagina; Di Stefano, Valeria; Fasanaro, Pasquale; Greco, Simona; Perfetti, Alessandra; Capogrossi, Maurizio C.; Gaetano, Carlo

    2014-01-01

    Abstract Aims: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. Results: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66Shc-null mice displayed decreased tissue damage following ischemia. Innovation: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. Conclusions: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. Antioxid. Redox Signal. 21, 1177–1188. PMID:23931770

  19. Intrinsic vascular dopamine - a key modulator of hypoxia-induced vasodilatation in splanchnic vessels.

    Science.gov (United States)

    Pfeil, Uwe; Kuncova, Jitka; Brüggmann, Doerthe; Paddenberg, Renate; Rafiq, Amir; Henrich, Michael; Weigand, Markus A; Schlüter, Klaus-Dieter; Mewe, Marco; Middendorff, Ralf; Slavikova, Jana; Kummer, Wolfgang

    2014-04-15

    Dopamine not only is a precursor of the catecholamines noradrenaline and adrenaline but also serves as an independent neurotransmitter and paracrine hormone. It plays an important role in the pathogenesis of hypertension and is a potent vasodilator in many mammalian systemic arteries, strongly suggesting an endogenous source of dopamine in the vascular wall. Here we demonstrated dopamine, noradrenaline and adrenaline in rat aorta and superior mesenteric arteries (SMA) by radioimmunoassay. Chemical sympathectomy with 6-hydroxydopamine showed a significant reduction of noradrenaline and adrenaline, while dopamine levels remained unaffected. Isolated endothelial cells were able to synthesize and release dopamine upon cAMP stimulation. Consistent with these data, mRNAs coding for catecholamine synthesizing enzymes, i.e. tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase, and dopamine-β-hydroxylase were detected by RT-PCR in cultured endothelial cells from SMA. TH protein was detected by immunohistochemisty and Western blot. Exposure of endothelial cells to hypoxia (1% O2) increased TH mRNA. Vascular smooth muscle cells partially expressed catecholaminergic traits. A physiological role of endogenous vascular dopamine was shown in SMA, where D1 dopamine receptor blockade abrogated hypoxic vasodilatation. Experiments on SMA with endothelial denudation revealed a significant contribution of the endothelium, although subendothelial dopamine release dominated. From these results we conclude that endothelial cells and cells of the underlying vascular wall synthesize and release dopamine in an oxygen-regulated manner. In the splanchnic vasculature, this intrinsic non-neuronal dopamine is the dominating vasodilator released upon lowering of oxygen tension.

  20. Modulating the bone marrow microenvironment:the role of DLL4:Notch signaling and hypoxia

    OpenAIRE

    Remédio, Leonor

    2013-01-01

    Tese de doutoramento, Biologia (Biologia Celular), Universidade de Lisboa, Faculdade de Ciências, 2013 Both cell-intrinsic and environmental cues drive hematopoiesis, which in adult mammals occurs mainly in the bone marrow (BM). BM endothelial cells that line the blood vessels contribute towards the regulation of hematopoiesis. In this Thesis, we used two strategies previously shown to increase vessel numbers, to assess the modulation of the BM “vascular niche” and its effects in hematopoi...

  1. CD133 Modulate HIF-1α Expression under Hypoxia in EMT Phenotype Pancreatic Cancer Stem-Like Cells

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    Koki Maeda

    2016-06-01

    Full Text Available Although CD133 is a known representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia is not fully known. The aim of this study is to demonstrate that CD133 regulates hypoxia inducible factor (HIF-1α expression with tumor migration. The CD133+ pancreatic cancer cell line, Capan1M9, was compared with the CD133− cell line, shCD133M9, under hypoxia. HIF-1α expression levels were compared by Western blot, HIF-1α nucleus translocation assay and real-time (RT-PCR. The hypoxia responsive element (HRE was observed by luciferase assay. The migration ability was analyzed by migration and wound healing assays. Epithelial mesenchymal transition (EMT related genes were analyzed by real-time RT-PCR. HIF-1α was highly expressed in Capan1M9 compared to shCD133M9 under hypoxia because of the high activation of HRE. Furthermore, the migration ability of Capan1M9 was higher than that of shCD133M9 under hypoxia, suggesting higher expression of EMT related genes in Capan1M9 compared to shCD133M9. Conclusion: HIF-1α expression under hypoxia in CD133+ pancreatic cancer cells correlated with tumor cell migration through EMT gene expression. Understanding the function of CD133 in cancer aggressiveness provides a novel therapeutic approach to eradicate pancreatic cancer stem cells.

  2. Gestures modulate speech processing early in utterances.

    Science.gov (United States)

    Wu, Ying Choon; Coulson, Seana

    2010-05-12

    Electroencephalogram was recorded as healthy adults viewed short videos of spontaneous discourse in which a speaker used depictive gestures to complement information expressed through speech. Event-related potentials were computed time-locked to content words in the speech stream and to subsequent related and unrelated picture probes. Gestures modulated event-related potentials to content words co-timed with the first gesture in a discourse segment, relative to the same words presented with static freeze frames of the speaker. Effects were observed 200-550 ms after speech onset, a time interval associated with semantic processing. Gestures also increased sensitivity to picture probe relatedness. Effects of gestures on picture probe and spoken word analysis were inversely correlated, suggesting that gestures differentially impact verbal and image-based processes.

  3. 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...

  4. 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...

  5. Insulin- and Warts-Dependent Regulation of Tracheal Plasticity Modulates Systemic Larval Growth during Hypoxia in Drosophila melanogaster

    Science.gov (United States)

    Wong, Daniel M.; Shen, Zhouyang; Owyang, Kristin E.; Martinez-Agosto, Julian A.

    2014-01-01

    Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability. PMID:25541690

  6. Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Daniel M Wong

    Full Text Available Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability.

  7. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

    Science.gov (United States)

    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans.

  8. Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.

    Science.gov (United States)

    Watzlawik, Jens O; Kahoud, Robert J; O'Toole, Ryan J; White, Katherine A M; Ogden, Alyssa R; Painter, Meghan M; Wootla, Bharath; Papke, Louisa M; Denic, Aleksandar; Weimer, Jill M; Carey, William A; Rodriguez, Moses

    2015-01-01

    Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P) 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life, followed by

  9. Hypoxia-activated genes from early placenta are elevated in Preeclampsia, but not in Intra-Uterine Growth Retardation

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    Danan Jean-Louis

    2005-08-01

    Full Text Available Abstract Background As a first step to explore the possible relationships existing between the effects of low oxygen pressure in the first trimester placenta and placental pathologies developing from mid-gestation, two subtracted libraries totaling 2304 cDNA clones were constructed. For achieving this, two reciprocal suppressive/subtractive hybridization procedures (SSH were applied to early (11 weeks human placental villi after incubation either in normoxic or in hypoxic conditions. The clones from both libraries (1440 hypoxia-specific and 864 normoxia-specific were spotted on nylon macroarrays. Complex cDNAs probes prepared from placental villi (either from early pregnancy, after hypoxic or normoxic culture conditions, or near term for controls or pathological placentas were hybridized to the membranes. Results Three hundred and fifty nine clones presenting a hybridization signal above the background were sequenced and shown to correspond to 276 different genes. Nine of these genes are mitochondrial, while 267 are nuclear. Specific expression profiles characteristic of preeclampsia (PE could be identified, as well as profiles specific of intra-uterine growth retardation (IUGR. Focusing on the chromosomal distribution of the fraction of genes that responded in at least one hybridization experiment, we could observe a highly significant chromosomal clustering of 54 genes into 8 chromosomal regions, four of which containing imprinted genes. Comparative mapping data indicate that these imprinted clusters are maintained in synteny in mice, and apparently in cattle and pigs, suggesting that the maintenance of such syntenies is requested for achieving a normal placental physiology in eutherian mammals. Conclusion We could demonstrate that genes induced in PE were also genes highly expressed under hypoxic conditions (P = 5.10-5, which was not the case for isolated IUGR. Highly expressed placental genes may be in syntenies conserved interspecifically

  10. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

    Science.gov (United States)

    Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

    2013-11-01

    Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep.

  11. MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Xue-Feng [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Respiration, Qinghai Provincial People' s Hospital, Xining (China); Wang, Hua; Xiao, Feng-Jun [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Yin, Yue [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Department of Hematology, Peking University First Hospital, Beijing (China); Xu, Qin-Qin [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Ge, Ri-Li, E-mail: geriligao@hotmail.com [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining 810001 (China); Wang, Li-Sheng, E-mail: wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China)

    2016-02-12

    MicroRNA-486 (miR-486) was first identified from human fetal liver cDNA library and validated as a regulator of hematopoiesis. Its roles in regulating the biological function of bone marrow-derived mesnechymal stem cells (BM-MSCs) under hypoxia have not been explored yet. In this study, we demonstrated that exposure to hypoxia upregulates miR-486 expression in BM-MSCs. Lentivirus-mediated overexpression of miR-486 resulted in increase of hepatocyte growth factor (HGF) and vascular endothelial growth factor(VEGF) in both mRNA and protein levels. MiR-486 expression also promotes proliferation and reduces apoptosis of BM-MSCs. Whereas MiR-486 knockdown downregulated the secretion of HGF and VEGF and induced apoptosis of BM-MSCs. Furthermore, PTEN-PI3K/AKT signaling was validated to be involved in changes of BM-MSC biological functions regulated by miR-486. These results suggested that MiR-486 mediated the hypoxia-induced angiogenic activity and promoted the proliferation and survival of BM-MSCs through regulating PTEN-PI3K/AKT signaling. These findings might provide a novel understanding of effective therapeutic strategy for hypoxic-ischemic diseases. - Highlights: • miR-486 is a hypoxia-induced miRNA. • miR-486 regulates the secretion of HGF and VEGF, promotes proliferation, and inhibits apoptosis of BM-MSCs. • miR-486 enhances PI3K/AKT activity signaling by targeting PTEN molecule.

  12. Hypothermia reduces VEGF-165 expression, but not osteogenic differentiation of human adipose stem cells under hypoxia

    Science.gov (United States)

    Bakker, Astrid D.; Hogervorst, Jolanda M. A.; Nolte, Peter A.; Klein-Nulend, Jenneke

    2017-01-01

    Cryotherapy is successfully used in the clinic to reduce pain and inflammation after musculoskeletal damage, and might prevent secondary tissue damage under the prevalent hypoxic conditions. Whether cryotherapy reduces mesenchymal stem cell (MSC) number and differentiation under hypoxic conditions, causing impaired callus formation is unknown. We aimed to determine whether hypothermia modulates proliferation, apoptosis, nitric oxide production, VEGF gene and protein expression, and osteogenic/chondrogenic differentiation of human MSCs under hypoxia. Human adipose MSCs were cultured under hypoxia (37°C, 1% O2), hypothermia and hypoxia (30°C, 1% O2), or control conditions (37°C, 20% O2). Total DNA, protein, nitric oxide production, alkaline phosphatase activity, gene expression, and VEGF protein concentration were measured up to day 8. Hypoxia enhanced KI67 expression at day 4. The combination of hypothermia and hypoxia further enhanced KI67 gene expression compared to hypoxia alone, but was unable to prevent the 1.2-fold reduction in DNA amount caused by hypoxia at day 4. Addition of hypothermia to hypoxic cells did not alter the effect of hypoxia alone on BAX-to-BCL-2 ratio, alkaline phosphatase activity, gene expression of SOX9, COL1, or osteocalcin, or nitric oxide production. Hypothermia decreased the stimulating effect of hypoxia on VEGF-165 gene expression by 6-fold at day 4 and by 2-fold at day 8. Hypothermia also decreased VEGF protein expression under hypoxia by 2.9-fold at day 8. In conclusion, hypothermia decreased VEGF-165 gene and protein expression, but did not affect differentiation, or apoptosis of MSCs cultured under hypoxia. These in vitro results implicate that hypothermia treatment in vivo, applied to alleviate pain and inflammation, is not likely to harm early stages of callus formation. PMID:28166273

  13. Assessing temporal and spatial variability of hypoxia over the inner Louisiana-upper Texas shelf: Application of an unstructured-grid three-dimensional coupled hydrodynamic-water quality model

    Science.gov (United States)

    Justić, Dubravko; Wang, Lixia

    2014-01-01

    Patterns of temporal and spatial variability in hypoxia (hypoxia originates in bottom waters on the mid-continental shelf, where isolated pockets of hypoxic water develop during early spring and later join into a larger continuous hypoxic zone. The model accurately described the seasonal cycle of hypoxia at station C6, including the episodes of intermittent hypoxia during May and June, persistent hypoxia during July and August, and dissipation of hypoxia during September. The onset of hypoxia coincided with high stability of the water column (i.e., Richardson number values>1) and the initial transition from normoxia (i.e., 6 mg O2 l-1) to hypoxia lasted about three weeks. The model results point to a significant short-term variability in the extent of hypoxic bottom waters, indicating that the size of the mid-summer hypoxic zone cannot be adequately captured by a single shelfwide cruise. The dynamics of bottom-water hypoxia is clearly influenced by the bathymetric features of the LaTex shelf, namely the presence of three shallow shoals (hypoxia on the LaTex shelf is strongly modulated by the frequency and intensity of cold fronts and tropical storms. High winds associated with these events disturb stratification, causing partial or complete breakdown of hypoxia. However, cold fronts and tropical storms also cause significant sediment resuspension that fuels respiration in the lower water column, and in this manner promote redevelopment of hypoxia.

  14. Hnf-1β transcription factor is an early hif-1α-independent marker of epithelial hypoxia and controls renal repair.

    Directory of Open Access Journals (Sweden)

    Stanislas Faguer

    Full Text Available Epithelial repair following acute kidney injury (AKI requires epithelial-mesenchyme-epithelial cycling associated with transient re-expression of genes normally expressed during kidney development as well as activation of growth factors and cytokine-induced signaling. In normal kidney, the Hnf-1β transcription factor drives nephrogenesis, tubulogenesis and epithelial homeostasis through the regulation of epithelial planar cell polarity and expression of developmental or tubular segment-specific genes. In a mouse model of ischemic AKI induced by a 2-hours hemorrhagic shock, we show that expression of this factor is tightly regulated in the early phase of renal repair with a biphasic expression profile (early down-regulation followed by transient over-expression. These changes are associated to tubular epithelial differentiation as assessed by KSP-cadherin and megalin-cubilin endocytic complex expression analysis. In addition, early decrease in Hnf1b expression is associated with the transient over-expression of one of its main target genes, the suppressor of cytokine signaling Socs3, which has been shown essential for renal repair. In vitro, hypoxia induced early up-regulation of Hnf-1β from 1 to 24 hours, independently of the hypoxia-inducible factor Hif-1α. When prolonged, hypoxia induced Hnf-1β down-regulation while normoxia led to Hnf-1β normalization. Last, Hnf-1β down-regulation using RNA interference in HK-2 cells led to phenotype switch from an epithelial to a mesenchyme state. Taken together, we showed that Hnf-1β may drive recovery from ischemic AKI by regulating both the expression of genes important for homeostasis control during organ repair and the state of epithelial cell differentiation.

  15. Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia.

    Science.gov (United States)

    Zhai, W; Sun, Y; Jiang, M; Wang, M; Gasiewicz, T A; Zheng, J; Chang, C

    2016-09-15

    It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.

  16. Substrate modulation of fatty acid effects on energization and respiration of kidney proximal tubules during hypoxia/reoxygenation.

    Directory of Open Access Journals (Sweden)

    Anja Bienholz

    Full Text Available Kidney proximal tubules subjected to hypoxia/reoxygenation develop a nonesterified fatty acid-induced energetic deficit characterized by persistent partial mitochondrial deenergization that can be prevented and reversed by citric acid cycle substrates. To further assess the role of competition between fatty acids and substrates on inner membrane substrate carriers in the deenergization and the contribution to deenergization of fatty acid effects on respiratory function, digitonin-permeabilized rabbit and mouse tubules were studied using either addition of exogenous oleate after control normoxic incubation or increases of endogenous fatty acids produced by hypoxia/reoxygenation. The results demonstrated major effects of matrix oxaloacetate accumulation on succinate-supported energization and respiration and their modification by fatty acids. Improvements of energization in the presence of fatty acids by glutamate were shown to result predominantly from lowering matrix oxaloacetate rather than from amelioration of transmembrane cycling of fatty acids and uncoupling. Mouse tubules had 2.5 fold higher rates of succinate utilization, which resulted in stronger effects of oxaloacetate accumulation than rabbit tubules. Hypoxia/reoxygenation induced respiratory inhibition that was more severe for complex I-dependent substrates. Fatty acids themselves did not acutely contribute to this respiratory inhibition, but lowering them during 60 min. reoxygenation to allow recovery of ATP during that period alleviated it. These data clarify the basis for the nonesterified fatty acid-induced mitochondrial energetic deficit in kidney proximal tubules that impairs structural and functional recovery and provide insight into interactions that need to be considered in the design of substrate-based interventions to improve mitochondrial function.

  17. A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Stefania Merighi

    2005-10-01

    Full Text Available Hypoxia-inducible factor-1 (HIF-1 is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02, adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2 protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.

  18. 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

    2017-01-01

    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% FiO2, 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. PMID:28255159

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

    Science.gov (United States)

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

    2016-12-01

    Chronic placental hypoxia is one of the root causes of placental insufficiencies that result in pre-eclampsia and maternal hypertension. Chronic hypoxia causes disruption of trophoblast (TB) development, invasion into maternal decidua, and remodeling of maternal spiral arteries. The pregnant guinea pig shares several characteristics with humans such as hemomonochorial placenta, villous subplacenta, deep TB invasion, and remodeling of maternal arteries, and is an ideal animal model to study placental development. We hypothesized that chronic placental hypoxia of the pregnant guinea pig inhibits TB invasion and alters spiral artery remodeling. Time-mated pregnant guinea pigs were exposed to either normoxia (NMX) or three levels of hypoxia (HPX: 16%, 12%, or 10.5% O2) from 20 day gestation until midterm (39-40 days) or term (60-65 days). At term, HPX (10.5% O2) increased maternal arterial blood pressure (HPX 57.9 ± 2.3 vs. NMX 40.4 ± 2.3, P < 0.001), decreased fetal weight by 16.1% (P < 0.05), and increased both absolute and relative placenta weights by 10.1% and 31.8%, respectively (P < 0.05). At midterm, there was a significant increase in TB proliferation in HPX placentas as confirmed by increased PCNA and KRT7 staining and elevated ESX1 (TB marker) gene expression (P < 0.05). Additionally, quantitative image analysis revealed decreased invasion of maternal blood vessels by TB cells. In summary, this animal model of placental HPX identifies several aspects of abnormal placental development, including increased TB proliferation and decreased migration and invasion of TBs into the spiral arteries, the consequences of which are associated with maternal hypertension and fetal growth restriction.

  20. Utility-based early modulation of processing distracting stimulus information.

    Science.gov (United States)

    Wendt, Mike; Luna-Rodriguez, Aquiles; Jacobsen, Thomas

    2014-12-10

    Humans are selective information processors who efficiently prevent goal-inappropriate stimulus information to gain control over their actions. Nonetheless, stimuli, which are both unnecessary for solving a current task and liable to cue an incorrect response (i.e., "distractors"), frequently modulate task performance, even when consistently paired with a physical feature that makes them easily discernible from target stimuli. Current models of cognitive control assume adjustment of the processing of distractor information based on the overall distractor utility (e.g., predictive value regarding the appropriate response, likelihood to elicit conflict with target processing). Although studies on distractor interference have supported the notion of utility-based processing adjustment, previous evidence is inconclusive regarding the specificity of this adjustment for distractor information and the stage(s) of processing affected. To assess the processing of distractors during sensory-perceptual phases we applied EEG recording in a stimulus identification task, involving successive distractor-target presentation, and manipulated the overall distractor utility. Behavioral measures replicated previously found utility modulations of distractor interference. Crucially, distractor-evoked visual potentials (i.e., posterior N1) were more pronounced in high-utility than low-utility conditions. This effect generalized to distractors unrelated to the utility manipulation, providing evidence for item-unspecific adjustment of early distractor processing to the experienced utility of distractor information.

  1. Hypoxia, Monitoring, and Mitigation System

    Science.gov (United States)

    2014-05-01

    al., (2012). Short-term exposure to hypoxia for work and leisure activities in health and disease: which level of hypoxia is safe? Sleep Breath, 16...Altitude Illness. Emergency Medical Clinics of North America. (2):329-55, viii. Travel to a high altitude requires that the human body acclimatize to...preventable. Practitioners working in or advising those traveling to a high altitude must be familiar with the early recognition of symptoms, prompt

  2. Early expressions of hypoxia-inducible factor 1alpha and vascular endothelial growth factor increase the neuronal plasticity of activated endogenous neural stem cells after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Seung Song; Jong-Tae Park; Joo Young Na; Man-Seok Park; Jeong-Kil Lee; Min-Cheol Lee; Hyung-Seok Kim

    2014-01-01

    Endogenous neural stem cells become “activated” after neuronal injury, but the activation sequence and fate of endogenous neural stem cells in focal cerebral ischemia model are little known. We evaluated the relationships between neural stem cells and hypoxia-inducible fac-tor-1α and vascular endothelial growth factor expression in a photothromobotic rat stroke model using immunohistochemistry and western blot analysis. We also evaluated the chrono-logical changes of neural stem cells by 5-bromo-2′-deoxyuridine (BrdU) incorporation. Hypoxia-inducible factor-1α expression was initially increased from 1 hour after ischemic injury, followed by vascular endothelial growth factor expression. Hypoxia-inducible factor-1αimmunoreactivity was detected in the ipsilateral cortical neurons of the infarct core and peri-in-farct area. Vascular endothelial growth factor immunoreactivity was detected in bilateral cortex, but ipsilateral cortex staining intensity and numbers were greater than the contralateral cortex. Vascular endothelial growth factor immunoreactive cells were easily found along the peri-infarct area 12 hours after focal cerebral ischemia. The expression of nestin increased throughout the microvasculature in the ischemic core and the peri-infarct area in all experimental rats after 24 hours of ischemic injury. Nestin immunoreactivity increased in the subventricular zone during 12 hours to 3 days, and prominently increased in the ipsilateral cortex between 3-7 days. Nes-tin-labeled cells showed dual differentiation with microvessels near the infarct core and reactive astrocytes in the peri-infarct area. BrdU-labeled cells were increased gradually from day 1 in the ipsilateral subventricular zone and cortex, and numerous BrdU-labeled cells were observed in the peri-infarct area and non-lesioned cortex at 3 days. BrdU-labeled cells rather than neu-rons, were mainly co-labeled with nestin and GFAP. Early expressions of hypoxia-inducible factor-1α and

  3. Protein dynamics modulated electron transfer kinetics in early stage photosynthesis.

    Science.gov (United States)

    Kundu, Prasanta; Dua, Arti

    2013-01-28

    A recent experiment has probed the electron transfer kinetics in the early stage of photosynthesis in Rhodobacter sphaeroides for the reaction center of wild type and different mutants [Science 316, 747 (2007)]. By monitoring the changes in the transient absorption of the donor-acceptor pair at 280 and 930 nm, both of which show non-exponential temporal decay, the experiment has provided a strong evidence that the initial electron transfer kinetics is modulated by the dynamics of protein backbone. In this work, we present a model where the electron transfer kinetics of the donor-acceptor pair is described along the reaction coordinate associated with the distance fluctuations in a protein backbone. The stochastic evolution of the reaction coordinate is described in terms of a non-Markovian generalized Langevin equation with a memory kernel and Gaussian colored noise, both of which are completely described in terms of the microscopics of the protein normal modes. This model provides excellent fits to the transient absorption signals at 280 and 930 nm associated with protein distance fluctuations and protein dynamics modulated electron transfer reaction, respectively. In contrast to previous models, the present work explains the microscopic origins of the non-exponential decay of the transient absorption curve at 280 nm in terms of multiple time scales of relaxation of the protein normal modes. Dynamic disorder in the reaction pathway due to protein conformational fluctuations which occur on time scales slower than or comparable to the electron transfer kinetics explains the microscopic origin of the non-exponential nature of the transient absorption decay at 930 nm. The theoretical estimates for the relative driving force for five different mutants are in close agreement with the experimental estimates obtained using electrochemical measurements.

  4. 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.

  5. SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons

    Science.gov (United States)

    Plant, Leigh D; Marks, Jeremy D; Goldstein, Steve AN

    2016-01-01

    The mechanism for the earliest response of central neurons to hypoxia—an increase in voltage-gated sodium current (INa)—has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions. DOI: http://dx.doi.org/10.7554/eLife.20054.001 PMID:28029095

  6. Enhanced Firing in NTS Induced by Short-Term Sustained Hypoxia Is Modulated by Glia-Neuron Interaction.

    Science.gov (United States)

    Accorsi-Mendonça, Daniela; Almado, Carlos E L; Bonagamba, Leni G H; Castania, Jaci A; Moraes, Davi J A; Machado, Benedito H

    2015-04-29

    Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. Here we analyzed the effect of short-term SH (24 h, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation of rats. SH increased both the sympatho-inhibitory and bradycardiac components of baroreflex and the sympathetic and respiratory responses of peripheral chemoreflex. Electrophysiological properties and synaptic transmission in the nucleus tractus solitarius (NTS) neurons, the first synaptic station of afferents of baroreflexes and chemoreflexes, were evaluated using brainstem slices and whole-cell patch-clamp. The second-order NTS neurons were identified by previous application of fluorescent tracer onto carotid body for chemoreceptor afferents or onto aortic depressor nerve for baroreceptor afferents. SH increased the intrinsic excitability of NTS neurons. Delayed excitation, caused by A-type potassium current (IKA), was observed in most of NTS neurons from control rats. The IKA amplitude was higher in identified second-order NTS neurons from control than in SH rats. SH also blunted the astrocytic inhibition of IKA in NTS neurons and increased the synaptic transmission in response to afferent fibers stimulation. The frequency of spontaneous excitatory currents was also increased in neurons from SH rats, indicating that SH increased the neurotransmission by presynaptic mechanisms. Therefore, short-term SH changed the glia-neuron interaction, increasing the excitability and excitatory transmission of NTS neurons, which may contribute to the observed increase in the reflex sensitivity of baroreflex and chemoreflex in in situ preparation.

  7. Different Levels of Hypoxia Tolerance during Early Life History Stages of Key Fish Species from the Northern Benguela Upwelling Ecosystem Inferred from the Comparison of Eco-Physiological Traits

    Science.gov (United States)

    Geist, S. J.; Imam, R. M.; Kunzmann, A.; Ekau, W.

    2016-02-01

    Global change factors such as a pronounced Oxygen Minimum Zone and the shoaling of hypoxic waters are assumed to play a major role in controlling the recruitment of fish stocks in Upwelling Systems by affecting the planktonic early life history stages. Ecological and ecophysiological traits in the larval stages of five key fish species in the Northern Benguela Upwelling System (Sardine, Sardinops sagax; Anchovy, Engraulis encrasicolus; Cape horse mackerel, Trachurus capensis; Cape hake, Merluccius sp.; Pelagic goby, Sufflogobobius bibarbatus) were investigated during the GENUS (Geochemistry and Ecology of the Namibian Upwelling Ecosystem) research project . Analysis of vertical larval distributions in relation to the depth of hypoxic water layers showed gradual interspecific differences, suggesting lower hypoxia tolerance levels of the small pelagics Sardine and Anchovy. Cape horse mackerel juveniles and larvae exhibited very high tolerance levels to short-term hypoxia in respirometry stress experiments, close to the levels of the extremely hypoxia-tolerant Pelagic goby. In the latter two species, we also measured the highest activities of anaerobic enzymes (pyruvate kinase and lactate dehydrogenase) in early and late larval stages, compared to very low activities in Sardine larvae. A higher amount of anaerobic enzymatic activity is related to a higher capacity to break down metabolites that build up during phases of oxygen debt and thus help the larvae to quickly recover from hypoxia exposure. In consequence, a high hypoxia tolerance during their early life stages allows Cape horse mackerel and Pelagic goby to successfully reproduce in an environment characterized by frequent hypoxic events. The low hypoxia tolerance of Sardine larvae, eventually resulting in higher mortality rates, is likely to be an important factor to understand the poor reproductive success and continuing recruitment failures of this formerly dominant fish species of the NBUS during the last

  8. Early effects of reward anticipation are modulated by dopaminergic stimulation.

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    Thore Apitz

    Full Text Available The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2 × 2 factorial design, while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude emerged at ∼ 100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20-30 Hz and low (13-20 Hz beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine.

  9. Early handling modulates outcome of neonatal dexamethasone exposure.

    Science.gov (United States)

    Claessens, Sanne E F; Daskalakis, Nikolaos P; Oitzl, Melly S; de Kloet, E Ronald

    2012-09-01

    Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1-21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1-3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Musical expertise modulates early processing of syntactic violations in language

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    Ahren B. Fitzroy

    2013-01-01

    Full Text Available Syntactic violations in speech and music have been shown to elicit an anterior negativity (AN as early as 100 ms after violation onset and a posterior positivity that peaks at roughly 600 ms (P600/LPC. The language AN is typically reported as left-lateralized (LAN, whereas the music AN is typically reported as right-lateralized (RAN. However, several lines of evidence suggest syntactic processing of language and music rely on overlapping neural systems. The current study tested the hypothesis that syntactic processing of speech and music share neural resources by examining whether musical proficiency modulates ERP indices of linguistic syntactic processing. ERPs were measured in response to syntactic violations in sentences and chord progressions in musicians and nonmusicians. Violations in speech were insertion errors in normal and semantically impoverished English sentences. Violations in music were out-of-key chord substitutions from distantly and closely related keys. Phrase-structure violations elicited an AN and P600 in both groups. Harmonic violations elicited an LPC in both groups, blatant harmonic violations also elicited a RAN in musicians only. Cross-domain effects of musical proficiency were similar to previously reported within-domain effects of linguistic proficiency on the distribution of the language AN; syntactic violations in normal English sentences elicited a left-lateralized AN in musicians and a bilateral AN in nonmusicians. The late positivities elicited by violations differed in latency and distribution between domains. These results suggest that initial processing of syntactic violations in language and music relies on shared neural resources in the general population, and that musical expertise results in more specialized cortical organization of syntactic processing in both domains.

  11. Emotional sounds modulate early neural processing of emotional pictures

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    Antje B M Gerdes

    2013-10-01

    Full Text Available In our natural environment, emotional information is conveyed by converging visual and auditory information; multimodal integration is of utmost importance. In the laboratory, however, emotion researchers have mostly focused on the examination of unimodal stimuli. Few existing studies on multimodal emotion processing have focused on human communication such as the integration of facial and vocal expressions. Extending the concept of multimodality, the current study examines how the neural processing of emotional pictures is influenced by simultaneously presented sounds. Twenty pleasant, unpleasant, and neutral pictures of complex scenes were presented to 22 healthy participants. On the critical trials these pictures were paired with pleasant, unpleasant and neutral sounds. Sound presentation started 500 ms before picture onset and each stimulus presentation lasted for 2s. EEG was recorded from 64 channels and ERP analyses focused on the picture onset. In addition, valence, and arousal ratings were obtained. Previous findings for the neural processing of emotional pictures were replicated. Specifically, unpleasant compared to neutral pictures were associated with an increased parietal P200 and a more pronounced centroparietal late positive potential (LPP, independent of the accompanying sound valence. For audiovisual stimulation, increased parietal P100 and P200 were found in response to all pictures which were accompanied by unpleasant or pleasant sounds compared to pictures with neutral sounds. Most importantly, incongruent audiovisual pairs of unpleasant pictures and pleasant sounds enhanced parietal P100 and P200 compared to pairings with congruent sounds. Taken together, the present findings indicate that emotional sounds modulate early stages of visual processing and, therefore, provide an avenue by which multimodal experience may enhance perception.

  12. Hypoxia and fatty liver.

    Science.gov (United States)

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

    2014-11-07

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

  13. An early-life hypoxia event has a long-term impact on protein digestion and growth in European sea bass juvenile.

    Science.gov (United States)

    Zambonino-Infante, José L; Mazurais, David; Servili, A; Cahu, C; Vanderplancke, G; Le Bayon, N; Huelvan, C; Claireaux, Guy

    2017-03-16

    Ocean warming, eutrophication and consequent decrease in oxygen lead to smaller average fish size. Although such responses are well-known in an evolutionary context, involving multiple generations, it appears to be incompatible with current rapid environmental change. Rather, phenotypic plasticity could provide a means for marine fish to cope with rapid environmental changes. However, little is known about the mechanisms underlying plastic responses to environmental conditions that favour small phenotypes.Our aim was to investigate how and why European sea bass that had experienced a short episode of moderate hypoxia during their larval stage subsequently exhibited a growth depression at the juvenile stage compared to the control group.We examined whether energy was used to cover higher costs for maintenance, digestion or activity metabolisms, as a result of differing metabolic rate. The lower growth was not a consequence of lower feed intake.We measured several respirometry parameters and we only found a higher SDA (Specific Dynamic Action) duration and lower SDA amplitude in a fish phenotype with lower growth; this phenotype was also associated with a lower protein digestive capacity in the intestine.Our results contribute to the understanding of the observed decrease in growth in response to climate change. They demonstrate that the reduced growth of juvenile fishes as a consequence of an early-life hypoxia event was not due to a change of fish aerobic scope, but to a specific change in the efficiency of protein digestive functions. The question remains of whether this effect is epigenetic and could be reversible in the offspring.

  14. EF5 PET of Tumor Hypoxia: A Predictive Imaging Biomarker of Response to Stereotactic Ablative Radiotherapy (SABR) for Early Lung Cancer

    Science.gov (United States)

    2016-09-01

    Award Number: W81XWH-12-1-0236 TITLE: : EF5 PET of Tumor Hypoxia: A Predictive Imaging Biomarker of Response to Stereotactic Ablative...2. REPORT TYPE Annual 3. DATES COVERED 15Aug2015 - 14Aug2016 4. TITLE AND SUBTITLE EF5 PET of Tumor Hypoxia: A Predictive Imaging Biomarker of 5a...comorbidities that increase surgical risk. Tumor hypoxia is a major known mechanism of radiation resistance and is especially expected to affect very short

  15. Hypoxia-inducible factor-1 modulates the expression of vascular endothelial growth factor and endothelial nitric oxide synthase induced by eccentric exercise.

    Science.gov (United States)

    Rodriguez-Miguelez, Paula; Lima-Cabello, Elena; Martínez-Flórez, Susana; Almar, Mar; Cuevas, María J; González-Gallego, Javier

    2015-04-15

    The present study investigated the effects of acute and chronic eccentric exercise on the hypoxia-inducible factor (HIF)-1α activation response and the concomitant modulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression in rat skeletal muscle. Twenty-four male Wistar rats were randomly assigned to three experimental groups: rested control group, acutely exercised group after an intermittent downhill protocol for 90 min, and acutely exercise group with a previous eccentric training of 8 wk. HIF-1α activation, VEGF and eNOS gene expression, protein content, and promoter activation were assessed in vastus lateralis muscle biopsies. Acute eccentric exercise induced a marked activation of HIF-1α and resulted in increased VEGF and eNOS mRNA level and protein concentration. The binding of HIF-1α to the VEGF and eNOS promoters, measured by a chromatin immunoprecipitation assay, was undetectable in rested rats, whereas it was evident in acutely exercised animals. Acute exercise also increased myeloperoxidase, toll-like receptor-4, tumor necrosis factor-α, and interleukin-1β protein content, suggesting a contribution of proinflammatory stimuli to HIF-1α activation and VEGF overexpression. All of these effects were partially abolished by training. Moreover, training resulted in an increased capillary density. In summary, our findings indicate that eccentric exercise prompts an HIF-1α response in untrained skeletal muscle that contributes to the upregulation of VEGF and eNOS gene expression and is attenuated after an eccentric training program. Copyright © 2015 the American Physiological Society.

  16. Polyamine biosynthesis and degradation are modulated by exogenous gamma-aminobutyric acid in root-zone hypoxia-stressed melon roots.

    Science.gov (United States)

    Wang, Chunyan; Fan, Longquan; Gao, Hongbo; Wu, Xiaolei; Li, Jingrui; Lv, Guiyun; Gong, Binbin

    2014-09-01

    We detected physiological change and gene expression related to PA metabolism in melon roots under controlled and hypoxic conditions with or without 5 mM GABA. Roots with hypoxia treatment showed a significant increase in glutamate decarboxylase (GAD) activity and endogenous GABA concentration. Concurrently, PA biosynthesis and degradation accelerated with higher gene expression and enzymes activity. However, endogenous GABA concentrations showed a large and rapid increase in Hypoxia + GABA treated roots. This led to a marked increase in Glu concentration by feedback inhibition of GAD activity. Hypoxia + GABA treatment enhanced arginine (Arg), ornithine (Orn) and methionine (Met) levels, promoting enzyme gene expression levels and arginine decarboxylase (ADC), ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activities in roots. Hypoxia + GABA treatment significantly increased concentrations of free putrescine (Put), spermidine (Spd) and spermine (Spm) from day two to eight, promoting the PA conversion to soluble conjugated and insoluble bound forms. However, PA degradation was significantly inhibited in hypoxia + GABA treated roots by significantly decreasing gene expression and activity of diamine oxidase (DAO) and polyamine oxidase (PAO). However, exogenous GABA showed a reduced effect in control compared with hypoxic conditions. Our data suggest that alleviating effect of exogenous GABA to hypoxia is closely associated with physiological regulation of PA metabolism. We propose a potential negative feedback mechanism of higher endogenous GABA levels from combined effects of hypoxia and exogenous GABA, which alleviate the hypoxia damage by accelerating PA biosynthesis and conversion as well as preventing PA degradation in melon plants.

  17. Effect of oxygen on cardiac differentiation in mouse iPS cells: role of hypoxia inducible factor-1 and Wnt/beta-catenin signaling.

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    Tanya L Medley

    Full Text Available BACKGROUND: Disturbances in oxygen levels have been found to impair cardiac organogenesis. It is known that stem cells and differentiating cells may respond variably to hypoxic conditions, whereby hypoxia may enhance stem cell pluripotency, while differentiation of multiple cell types can be restricted or enhanced under hypoxia. Here we examined whether HIF-1alpha modulated Wnt signaling affected differentiation of iPS cells into beating cardiomyocytes. OBJECTIVE: We investigated whether transient and sustained hypoxia affects differentiation of cardiomyocytes derived from murine induced pluripotent stem (iPS cells, assessed the involvement of HIF-1alpha (hypoxia-inducible factor-1alpha and the canonical Wnt pathway in this process. METHODS: Embryoid bodies (EBs derived from iPS cells were differentiated into cardiomyocytes and were exposed either to 24 h normoxia or transient hypoxia followed by a further 13 days of normoxic culture. RESULTS: At 14 days of differentiation, 59 ± 2% of normoxic EBs were beating, whilst transient hypoxia abolished beating at 14 days and EBs appeared immature. Hypoxia induced a significant increase in Brachyury and islet-1 mRNA expression, together with reduced troponin C expression. Collectively, these data suggest that transient and sustained hypoxia inhibits maturation of differentiating cardiomyocytes. Compared to normoxia, hypoxia increased HIF-1alpha, Wnt target and ligand genes in EBs, as well as accumulation of HIF-1alpha and beta-catenin in nuclear protein extracts, suggesting involvement of the Wnt/beta-catenin pathway. CONCLUSION: Hypoxia impairs cardiomyocyte differentiation and activates Wnt signaling in undifferentiated iPS cells. Taken together the study suggests that oxygenation levels play a critical role in cardiomyocyte differentiation and suggest that hypoxia may play a role in early cardiogenesis.

  18. MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.

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    Xiaomeng Zhang

    Full Text Available TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC. The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE and diffusion weighted (DW magnetic resonance imaging (MRI were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3 following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.

  19. Hypoxia-regulated target genes implicated in tumor metastasis

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    Tsai Ya-Ping

    2012-12-01

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

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

    Science.gov (United States)

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

    2016-09-08

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

  1. Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling.

    Science.gov (United States)

    Haga, Christopher L; Velagapudi, Sai Pradeep; Strivelli, Jacqueline R; Yang, Wang-Yong; Disney, Matthew D; Phinney, Donald G

    2015-10-16

    Hypoxia induces a complex circuit of gene expression that drives tumor progression and increases drug resistance. Defining these changes allows for an understanding of how hypoxia alters tumor biology and informs design of lead therapeutics. We probed the role of microRNA-544 (miR-544), which silences mammalian target of rapamycin (mTOR), in a hypoxic breast cancer model by using a small molecule (1) that selectively impedes the microRNA's biogenesis. Application of 1 to hypoxic tumor cells selectively inhibited production of the mature microRNA, sensitized cells to 5-fluorouracil, and derepressed mRNAs affected by miR-544 in cellulo and in vivo, including boosting mTOR expression. Thus, small molecule inhibition of miR-544 reverses a tumor cell's physiological response to hypoxia. Importantly, 1 sensitized tumor cells to hypoxia-associated apoptosis at a 25-fold lower concentration than a 2'-O-methyl RNA antagomir and was as selective. Further, the apoptotic effect of 1 was suppressed by treatment of cell with rapamycin, a well-known inhibitor of the mTOR signaling pathway, illustrating the selectivity of the compound. Thus, RNA-directed chemical probes, which could also serve as lead therapeutics, enable interrogation of complex cellular networks in cells and animals.

  2. Intermodal auditory, visual, and tactile attention modulates early stages of neural processing.

    Science.gov (United States)

    Karns, Christina M; Knight, Robert T

    2009-04-01

    We used event-related potentials (ERPs) and gamma band oscillatory responses (GBRs) to examine whether intermodal attention operates early in the auditory, visual, and tactile modalities. To control for the effects of spatial attention, we spatially coregistered all stimuli and varied the attended modality across counterbalanced blocks in an intermodal selection task. In each block, participants selectively responded to either auditory, visual, or vibrotactile stimuli from the stream of intermodal events. Auditory and visual ERPs were modulated at the latencies of early cortical processing, but attention manifested later for tactile ERPs. For ERPs, auditory processing was modulated at the latency of the Na (29 msec), which indexes early cortical or thalamocortical processing and the subsequent P1 (90 msec) ERP components. Visual processing was modulated at the latency of the early phase of the C1 (62-72 msec) thought to be generated in the primary visual cortex and the subsequent P1 and N1 (176 msec). Tactile processing was modulated at the latency of the N160 (165 msec) likely generated in the secondary association cortex. Intermodal attention enhanced early sensory GBRs for all three modalities: auditory (onset 57 msec), visual (onset 47 msec), and tactile (onset 27 msec). Together, these results suggest that intermodal attention enhances neural processing relatively early in the sensory stream independent from differential effects of spatial and intramodal selective attention.

  3. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

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

  4. Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers

    Energy Technology Data Exchange (ETDEWEB)

    Henriques de Figueiredo, B. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); INCIA UMR-CNRS 5287, Bordeaux (France); Zacharatou, C. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); Galland-Girodet, S.; Benech, J. [Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Clermont-Gallerande, H. de [Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); Lamare, F. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Hatt, M. [LaTIM INSERM U1101, Brest (France); Digue, L. [Hospital Saint-Andre, Department of Clinical Oncology, CHRU Bordeaux (France); Mones del Pujol, E. de [Department of Oto-rhino-laryngology, CHRU Bordeaux (France); Fernandez, P. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); University Bordeaux 2, Bordeaux (France)

    2014-09-23

    Positron emission tomography (PET) with [{sup 18}F]-fluoromisonidazole ([{sup 18}F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [{sup 18}F]-FMISO-PET for head-and-neck cancers (HNC). Ten patients with inoperable stages III-IV HNC underwent [{sup 18}F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8 % respectively. A dose escalation up to 79.8 Gy guided by [{sup 18}F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids. (orig.) [German] Die Positronenemissionstomographie (PET) mit [{sup 18}F]-Fluoromisonidazol ([{sup 18}F]-FMISO) ermoeglicht eine nichtinvasive Beurteilung der Hypoxie. Ziel dieser Studie ist es, die Durchfuehrbarkeit einer [{sup 18}F]-FMISO-PET-gefuehrten Dosissteigerung bei volumetrisch modulierter Arc-Therapie (VMAT) von Kopf-Hals-Tumoren (KHT) zu bewerten. Zehn Patienten mit inoperablen KHT der Stadien III-IV erhielten vor der Strahlentherapie eine [{sup 18}F]-FMISO-PET. Hypoxische Zielvolumina (HV) wurden automatisch mit Hilfe des FLAB(Fuzzy Locally Adaptive Bayesian

  5. The infectious hypoxia: occurrence and causes during Shigella infection.

    Science.gov (United States)

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

    2017-03-01

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

  6. Electrical neuroimaging reveals early generator modulation to emotional words.

    Science.gov (United States)

    Ortigue, Stephanie; Michel, Christoph M; Murray, Micah M; Mohr, Christine; Carbonnel, Serge; Landis, Theodor

    2004-04-01

    Functional electrical neuroimaging investigated incidental emotional word processing. Previous research suggests that the brain may differentially respond to the emotional content of linguistic stimuli pre-lexically (i.e., before distinguishing that these stimuli are words). We investigated the spatiotemporal brain mechanisms of this apparent paradox and in particular whether the initial differentiation of emotional stimuli is marked by different brain generator configurations using high-density, event-related potentials. Such would support the existence of specific cerebral resources dedicated to emotional word processing. A related issue concerns the possibility of right-hemispheric specialization in the processing of emotional stimuli. Thirteen healthy men performed a go/no-go lexical decision task with bilateral word/non-word or non-word/non-word stimulus pairs. Words included equal numbers of neutral and emotional stimuli, but subjects made no explicit discrimination along this dimension. Emotional words appearing in the right visual field (ERVF) yielded the best overall performance, although the difference between emotional and neutral words was larger for left than for right visual field presentations. Electrophysiologically, ERVF presentations were distinguished from all other conditions over the 100-140 ms period by a distinct scalp topography, indicative of different intracranial generator configurations. A distributed linear source estimation (LAURA) of this distinct scalp potential field revealed bilateral lateral-occipital sources with a right hemisphere current density maximum. These data support the existence of a specialized brain network triggered by the emotional connotation of words at a very early processing stage.

  7. Promoting Evidence-Based Practices: New Teaching Module for Early Childhood Teacher Educators

    Science.gov (United States)

    Young Children, 2009

    2009-01-01

    Linda Halgunseth, head of NAEYC's Office of Applied Research (OAR), tells readers about Child Care and Early Education Research Connections, a Web site (www.researchconnections.org/teaching_modules) to help teacher educators integrate knowledge about evidence-based practices into teacher education programs. In addition, the article touts the…

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

    Science.gov (United States)

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

    2012-01-01

    Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for 3 weeks (6 h/day). In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current potential shift was shortened after stress. Moreover, K+ fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K+ levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K+ channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance, and K+-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K+ accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K+ buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain. PMID:22470344

  9. Hypoxia induces apelin expression in human adipocytes.

    Science.gov (United States)

    Geiger, K; Muendlein, A; Stark, N; Saely, C H; Wabitsch, M; Fraunberger, P; Drexel, H

    2011-06-01

    Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Function and modulation of premotor brainstem parasympathetic cardiac neurons that control heart rate by hypoxia-, sleep-, and sleep-related diseases including obstructive sleep apnea.

    Science.gov (United States)

    Dergacheva, Olga; Weigand, Letitia A; Dyavanapalli, Jhansi; Mares, Jacquelyn; Wang, Xin; Mendelowitz, David

    2014-01-01

    Parasympathetic cardiac vagal neurons (CVNs) in the brainstem dominate the control of heart rate. Previous work has determined that these neurons are inherently silent, and their activity is largely determined by synaptic inputs to CVNs that include four major types of synapses that release glutamate, GABA, glycine, or serotonin. Whereas prior reviews have focused on glutamatergic, GABAergic and glycinergic pathways, and the receptors in CVNs activated by these neurotransmitters, this review focuses on the alterations in CVN activity with hypoxia-, sleep-, and sleep-related cardiovascular diseases including obstructive sleep apnea.

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

    Institute of Scientific and Technical Information of China (English)

    裴建明; 毕辉; 王跃民; 朱妙章; 周京军; 朱运龙

    2003-01-01

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

  12. N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells

    Science.gov (United States)

    Lu, Binger; Wang, Bin; Zhong, Shuping; Zhang, Yanmei; Gao, Fenfei; Chen, Yicun; Zheng, Fuchun; Shi, Ganggang

    2016-01-01

    Endothelial cells are highly sensitive to hypoxia and contribute to myocardial ischemia/reperfusion injury. We have reported that N-n-butyl haloperidol iodide (F2) can attenuate hypoxia/reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs). However, the molecular mechanisms remain unclear. Neonatal rat CMECs were isolated and subjected to H/R. Pretreatment of F2 leads to a reduction in H/R injury, as evidenced by increased cell viability, decreased lactate dehydrogenase (LDH) leakage and apoptosis, together with enhanced AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1) phosphorylation in H/R ECs. Blockade of AMPK with compound C reversed F2-induced inhibition of H/R injury, as evidenced by decreased cell viability, increased LDH release and apoptosis. Moreover, compound C also blocked the ability of F2 to reduce H/R-induced reactive oxygen species (ROS) generation. Supplementation with the ROS scavenger N-acetyl-L-cysteine (NAC) reduced ROS levels, increased cell survival rate, and decreased both LDH release and apoptosis after H/R. In conclusion, our data indicate that F2 may mitigate H/R injury by stimulating LKB1/AMPK signaling pathway and subsequent suppression of ROS production in CMECs. PMID:27166184

  13. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

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

    2016-01-01

    Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular...... response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations...... in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...

  14. Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Ambrosio, Maria Raffaella; Sturli, Niccolò; Lonetto, Giuseppe; Rosati, Fabiana; Rocca, Bruno Jim; Ventimiglia, Giuseppina; del Vecchio, Maria Teresa; Prudovsky, Igor; Marchionni, Niccolò; Tarantini, Francesca

    2013-12-01

    Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the γ-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC.

  15. EF5 PET of Tumor Hypoxia: A Predictive Imaging Biomarker of Response to Stereotactic Ablative Radiotherapy (SABR) for Early Lung Cancer

    Science.gov (United States)

    2015-09-01

    that notwithstanding any other provision of law , no person shall be subject to any penalty for failing to comply with a collection of information if it... proportion of lung cancers at earlier stages, yet the aging of the population will lead to a greater proportion of patients having comorbidities that increase...of 9 including the parallel study patients) had imageable hypoxia as defined by our plan of analysis. With respect to the endpoint of imaging response

  16. Top-down modulation of human early visual cortex after stimulus offset supports successful postcued report.

    Science.gov (United States)

    Sergent, Claire; Ruff, Christian C; Barbot, Antoine; Driver, Jon; Rees, Geraint

    2011-08-01

    Modulations of sensory processing in early visual areas are thought to play an important role in conscious perception. To date, most empirical studies focused on effects occurring before or during visual presentation. By contrast, several emerging theories postulate that sensory processing and conscious visual perception may also crucially depend on late top-down influences, potentially arising after a visual display. To provide a direct test of this, we performed an fMRI study using a postcued report procedure. The ability to report a target at a specific spatial location in a visual display can be enhanced behaviorally by symbolic auditory postcues presented shortly after that display. Here we showed that such auditory postcues can enhance target-specific signals in early human visual cortex (V1 and V2). For postcues presented 200 msec after stimulus termination, this target-specific enhancement in visual cortex was specifically associated with correct conscious report. The strength of this modulation predicted individual levels of performance in behavior. By contrast, although later postcues presented 1000 msec after stimulus termination had some impact on activity in early visual cortex, this modulation no longer related to conscious report. These results demonstrate that within a critical time window of a few hundred milliseconds after a visual stimulus has disappeared, successful conscious report of that stimulus still relates to the strength of top-down modulation in early visual cortex. We suggest that, within this critical time window, sensory representation of a visual stimulus is still under construction and so can still be flexibly influenced by top-down modulatory processes.

  17. 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...

  18. Early Neural Markers of Implicit Attitudes: N170 Modulated by Intergroup and Evaluative Contexts in IAT

    Directory of Open Access Journals (Sweden)

    Agustin eIbanez

    2010-10-01

    Full Text Available The Implicit Association Test (IAT is the most popular measure to evaluate implicit attitudes. Nevertheless, its neural correlates are not yet fully understood. We examined event related potentials (ERPs in response to face- and word- processing while indigenous and non-indigenous participants performed an IAT displaying faces (ingroup and outgroup members and words (positive and negative valence as targets of category judgments. The N170 component was modulated by valence of words and by ingroup/outgroup face categorization. Contextual effects (face-words implicitly associated in the task had an influence on the N170 amplitude modulation. On the one hand, in face categorization, right N170 showed differences according to the association between social categories of faces and affective valence of words. On the other, in word categorization, left N170 presented a similar modulation when the task implied a negative valence associated with ingroup faces. Only indigenous participants showed a significant IAT effect and N170 differences. Our results demonstrate an early ERP blending of stimuli processing with both intergroup and evaluative contexts, suggesting an integration of contextual information related to intergroup attitudes during the early stages of word and face processing. To our knowledge, this is the first report of early ERPs during an ethnicity IAT, opening a new branch of exchange between social neuroscience and social psychology of attitudes.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-08-15

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

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

    Directory of Open Access Journals (Sweden)

    Neuhaus C

    2014-11-01

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

  1. Hypoxia-induced angiogenesis: good and evil.

    Science.gov (United States)

    Krock, Bryan L; Skuli, Nicolas; Simon, M Celeste

    2011-12-01

    The vascular network delivers oxygen (O(2)) and nutrients to all cells within the body. It is therefore not surprising that O(2) availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O(2) are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities.

  2. Vestibular activation differentially modulates human early visual cortex and V5/MT excitability and response entropy.

    Science.gov (United States)

    Seemungal, Barry M; Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC.

  3. Effect of intermittent hypoxic training on hypoxia tolerance based on single-channel EEG.

    Science.gov (United States)

    Zhang, Tinglin; Wang, You; Li, Guang

    2016-03-23

    A single-channel algorithm was proposed in order to study effect of intermittent hypoxic training on hypoxia tolerance based on EEG pattern. EEG was decomposed by ensemble empirical mode decomposition into a finite number of intrinsic mode functions (IMFs) based on the intrinsic local characteristic time scale. Analytic amplitude, analytic frequency, and recurrence property quantified by recurrence quantification analysis were explored on IMFs, and the first two scales revealed difference between normal EEG and hypoxia EEG. Classification accuracy of hypoxia EEG and normal EEG could reach 67.8% before decline of neurobehavioral ability, which represented that hypoxia EEG pattern could be detected at an early stage. Classification accuracy of hypoxia EEG and normal EEG increased with time and deepened intensity of hypoxia was observed by regular shift of hypoxia EEG pattern with time in a three dimensional subspace. The reduced shift and classification accuracy after intermittent hypoxic training represented that hypoxia tolerance enhanced.

  4. Hypoxia inducible factor-1α inhibition produced anti-allodynia effect and suppressed inflammatory cytokine production in early stage of mouse complex regional pain syndrome model.

    Science.gov (United States)

    Hsiao, Hung-Tsung; Lin, Ya-Chi; Wang, Jeffrey Chi-Fei; Tsai, Yu-Chuan; Liu, Yen-Chin

    2016-03-01

    Complex regional pain syndrome (CRPS) is related to microcirculation impairment associated with tissue hypoxia and peripheral cytokine overproduction in the affected limb. Previous studies suggest that the pathogenesis involves hypoxia inducible factor-1α (HIF-1α) and exaggerated regional inflammatory response. 1-methylpropyl 2-imidazolyl disulfide (PX-12) acts as the thioredoxin-1 (Trx-1) inhibitor and decreases the level of HIF-1α, and can rapidly be metabolized for Trx-1 redox inactivation. This study hypothesized that PX-12 can decrease the cytokine production for nociceptive sensitization in the hypoxia-induced pain model. CD1 mice weighing around 30 g were used. The animal CRPS model was developed via the chronic post-ischaemic pain (CPIP) model. The model was induced by using O-rings on the ankles of the mice hind limbs to produce 3-h ischaemia-reperfusion injury on the paw. PX-12 (25 mg/kg, 5 mg/kg) was given through tail vein injection immediately after ischaemia. Animal behaviour was tested using the von Frey method for 7 days. Local paw skin tissue was harvest from three groups (control, 5 mg/kg, 25 mg/kg) 2 h after injection of PX-12. The protein expression of interleukin-1β (IL-1β) and HIF-1α was analysed with the Western blotting method. Mice significantly present an anti-allodynia effect in a dose-related manner after the PX-12 administration. Furthermore, PX-12 not only decreased the expression of HIF-1α but also decreased the expression of IL-1β over the injured palm. This study, therefore, shows the first evidence of the anti-allodynia effect of PX-12 in a CPIP animal model for pain behaviour. The study concluded that inhibition of HIF-1α may produce an analgesic effect and the associated suppression of inflammatory cytokine IL-1β in a CPIP model. © 2016 John Wiley & Sons Australia, Ltd.

  5. Dosimetric comparison of hybrid volumetric-modulated arc therapy, volumetric-modulated arc therapy, and intensity-modulated radiation therapy for left-sided early breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Jia-Fu [Department of Radiation Physics, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yeh, Dah-Cherng [Department of General Surgery, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yeh, Hui-Ling, E-mail: hlyeh@vghtc.gov.tw [Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Chang, Chen-Fa [Department of Radiation Physics, Taichung Veterans General Hospital, Taichung, Taiwan (China); Lin, Jin-Ching [Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan (China)

    2015-10-01

    To compare the dosimetric performance of 3 different treatment techniques: hybrid volumetric-modulated arc therapy (hybrid-VMAT), pure-VMAT, and fixed-field intensity-modulated radiation therapy (F-IMRT) for whole-breast irradiation of left-sided early breast cancer. The hybrid-VMAT treatment technique and 2 other treatment techniques—pure-VMAT and F-IMRT—were compared retrospectively in 10 patients with left-sided early breast cancer. The treatment plans of these patients were replanned using the same contours based on the original computed tomography (CT) data sets. Dosimetric parameters were calculated to evaluate plan quality. Total monitor units (MUs) and delivery time were also recorded and evaluated. The hybrid-VMAT plan generated the best results in dose coverage of the target and the dose uniformity inside the target (p < 0.0001 for conformal index [CI]; p = 0.0002 for homogeneity index [HI] of planning target volume [PTV]{sub 50.4} {sub Gy} and p < 0.0001 for HI of PTV{sub 62} {sub Gy}). Volumes of ipsilateral lung irradiated to doses of 20 Gy (V{sub 20} {sub Gy}) and 5 Gy (V{sub 5} {sub Gy}) by the hybrid-VMAT plan were significantly less than those of the F-IMRT and the pure-VMAT plans. The volume of ipsilateral lung irradiated to a dose of 5 Gy was significantly less using the hybrid-VMAT plan than that using the F-IMRT or the pure-VMAT plan. The total mean MUs for the hybrid-VMAT plan were significantly less than those for the F-IMRT or the pure-VMAT plan. The mean machine delivery time was 3.23 ± 0.29 minutes for the hybrid-VMAT plans, which is longer than that for the pure-VMAT plans but shorter than that for the F-IMRT plans. The hybrid-VMAT plan is feasible for whole-breast irradiation of left-sided early breast cancer.

  6. 1H magnetic resonance spectroscopy metabolite profiles of neonatal rat hippocampus and brainstem regions following early postnatal exposure to intermittent hypoxia

    Science.gov (United States)

    Darnall, Robert A.; Chen, Xi; Nemani, Krishnamurthy V.; Sirieix, Chrystelle M.; Gimi, Barjor

    2017-03-01

    Most premature infants born at less than 30 weeks gestation are exposed to periods of mild intermittent hypoxia (IH) associated with apnea of prematurity and periodic breathing. In adults, IH associated with sleep apnea causes neurochemical and structural alterations in the brain. However, it is unknown whether IH in the premature infant leads to neurodevelopmental impairment. Quantification of biochemical markers that can precisely identify infants at risk of adverse neurodevelopmental outcome is essential. In vivo 1H magnetic resonance spectroscopy (1H MRS) facilitates the quantification of metabolites from distinct regions of the developing brain. We report the changes in metabolite profiles in the brainstem and hippocampal regions of developing rat brains, resulting from exposure to IH. Rat pups were chosen for study because there is rapid postnatal hippocampal development that occurs during the first 4 weeks in the developing rat brain, which corresponds to the first 2-3 postnatal years of development in humans. The brainstem was examined because of our interest in respiratory control disorders in the newborn and because of brainstem gliosis described in infants who succumb to Sudden Infant Death Syndrome (SIDS). Metabolite profiles were compared between hypoxia treated rat pups (n = 9) and normoxic controls (n = 6). Metabolite profiles were acquired using the Point-RESolved spectroscopy (PRESS) MRS sequence and were quantified using the TARQUIN software. There was a significant difference in the concentrations of creatine (p = 0.031), total creatine (creatine + phosphocreatine) (p = 0.028), and total choline (p = 0.001) in the brainstem, and glycine (p = 0.031) in the hippocampal region. The changes are consistent with altered cellular bioenergetics and metabolism associated with hypoxic insult.

  7. Early visual evoked potentials are modulated by eye position in humans induced by whole body rotations

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    Petit Laurent

    2004-09-01

    Full Text Available Abstract Background To reach and grasp an object in space on the basis of its image cast on the retina requires different coordinate transformations that take into account gaze and limb positioning. Eye position in the orbit influences the image's conversion from retinotopic (eye-centered coordinates to an egocentric frame necessary for guiding action. Neuroimaging studies have revealed eye position-dependent activity in extrastriate visual, parietal and frontal areas that is along the visuo-motor pathway. At the earliest vision stage, the role of the primary visual area (V1 in this process remains unclear. We used an experimental design based on pattern-onset visual evoked potentials (VEP recordings to study the effect of eye position on V1 activity in humans. Results We showed that the amplitude of the initial C1 component of VEP, acknowledged to originate in V1, was modulated by the eye position. We also established that putative spontaneous small saccades related to eccentric fixation, as well as retinal disparity cannot explain the effects of changing C1 amplitude of VEP in the present study. Conclusions The present modulation of the early component of VEP suggests an eye position-dependent activity of the human primary visual area. Our findings also evidence that cortical processes combine information about the position of the stimulus on the retinae with information about the location of the eyes in their orbit as early as the stage of primary visual area.

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

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    Neuhaus, Christopher; Hinkelbein, Jochen

    2014-01-01

    The aim of this narrative review is to provide an overview on cognitive responses to hypobaric hypoxia and to show relevant implications for aviation training. A principal element of hypoxia-awareness training is the intentional evocation of hypoxia symptoms during specific training sessions within a safe and controlled environment. Repetitive training should enable pilots to learn and recognize their personal hypoxia symptoms. A time span of 3-6 years is generally considered suitable to refresh knowledge of the more subtle and early symptoms especially. Currently, there are two different technical approaches available to induce hypoxia during training: hypobaric chamber training and reduced-oxygen breathing devices. Hypoxia training for aircrew is extremely important and effective, and the hypoxia symptoms should be emphasized clearly to aircrews. The use of tight-fitting masks, leak checks, and equipment checks should be taught to all aircrew and reinforced regularly. It is noteworthy that there are major differences in the required quality and quantity of hypoxia training for both military and civilian pilots.

  9. Volumetric modulated arc therapy for carotid sparing in the management of early glottic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Suk; Lee, Sol Min; Kim, Gwi Eon [Dept. of Radiation Oncology, Jeju National University Hospital, Jeju National University School of Medicine, Jeju (Korea, Republic of); Lee, Jae Gi; Park, Jong In; Sung, Won Mo [Program in Biomedical Radiation Sciences, Dept. of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul (Korea, Republic of)

    2016-03-15

    Radiotherapy of the neck is known to cause carotid artery stenosis. We compared the carotid artery dose received between volumetric modulated arc therapy (VMAT) and conventional fixed-field intensity-modulated radiotherapy (IMRT) plans in patients with early glottic cancer. Twenty-one early glottic cancer patients who previously underwent definitive radiotherapy were selected for this study. For each patient, double arc VMAT, 8-field IMRT, 3-dimensional conformal radiotherapy (3DCRT), and lateral parallel-opposed photon field radiotherapy (LPRT) plans were created. The 3DCRT plan was generated using lateral parallel-opposed photon fields plus an anterior photon field. VMAT and IMRT treatment plan optimization was performed under standardized conditions to obtain adequate target volume coverage and spare the carotid artery. Dose-volume specifications for the VMAT, IMRT, 3DCRT, and LPRT plans were calculated with radiotherapy planning system. Monitor units (MUs) and delivery time were measured to evaluate treatment efficiency. Target volume coverage and homogeneity results were comparable between VMAT and IMRT; however, VMAT was superior to IMRT for carotid artery dose sparing. The mean dose to the carotid arteries in double arc VMAT was reduced by 6.8% compared to fixed-field IMRT (p < 0.001). The MUs for VMAT and IMRT were not significantly different (p = 0.089). VMAT allowed an approximately two-fold reduction in treatment delivery time in comparison to IMRT (3 to 5 minutes vs. 5 to 10 minutes). VMAT resulted in a lower carotid artery dose compared to conventional fixed-field IMRT, and maintained good target coverage in patients with early glottic cancer.

  10. Effects of systemic hypoxia on human muscular adaptations to resistance exercise training

    OpenAIRE

    Kon, Michihiro; Ohiwa, Nao; Honda, Akiko; Matsubayashi, Takeo; Ikeda, Tatsuaki; Akimoto, Takayuki; Suzuki, Yasuhiro; Hirano, Yuichi; Russell, Aaron P.

    2014-01-01

    Abstract Hypoxia is an important modulator of endurance exercise‐induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise‐induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross‐sectional area (CSA), one‐repetition maximum (1RM), muscular endurance, and ma...

  11. Hypoxia-mediated metastasis.

    Science.gov (United States)

    Chang, Joan; Erler, Janine

    2014-01-01

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

  12. Enhanced susceptibility to seizures modulated by high interleukin-1β levels during early life malnutrition.

    Science.gov (United States)

    Simão, Fabrício; Habekost Oliveira, Victória; Lahourgue Nunes, Magda

    2016-10-01

    Early malnutrition in life has permanent consequences on brain development and has been suggested to influence seizure susceptibility. Despite malnutrition is not a direct cause of seizures, we hypothesize that malnutrition may modulate inflammatory response and result in cerebral vulnerability to seizures. In this study, we provide evidence that malnutrition may increase susceptibility to seizures in the postnatal period by interleukin-1β (IL-1β) in the hippocampus. Malnourished rats were maintained on a nutritional deprivation regimen from postnatal day 1 (P1) to P10. From P7 to P10, the threshold to seizures induced by flurothyl was used as an index of seizure susceptibility. ELISA and western blot was performed to evaluate levels of IL-1β, IL-1R1, PSD-95 and synapsin. The role of inflammation in the changes of seizure threshold was studied with inhibitors of IL-1β and IL-1R1. A significant decrease in body weight and seizure threshold was observed in postnatal malnourished rats. Early malnutrition modulates inflammation by high levels of IL-1β in hippocampus and in serum. Furthermore, our malnutrition paradigm induced an increase in corticosterone levels. Injection of IL-1β and IL-1R1 inhibitors before seizure induction augments seizure threshold in malnourished rats similar to nourished group. Malnutrition did not change PSD-95 and synapsin expression in the hippocampus. We suggest that malnutrition-induced inflammation might contribute to seizure susceptibility in the postnatal period. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1150-1159, 2016. © 2016 Wiley Periodicals, Inc.

  13. Early clinical experience with volumetric modulated arc therapy in head and neck cancer patients

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    Cozzi Luca

    2010-10-01

    Full Text Available Abstract Background To report about early clinical experience in radiation treatment of head and neck cancer of different sites and histology by volumetric modulated arcs with the RapidArc technology. Methods During 2009, 45 patients were treated at Istituto Clinico Humanitas with RapidArc (28 males and 17 females, median age 65 years. Of these, 78% received concomitant chemotherapy. Thirty-six patients were treated as exclusive curative intent (group A, three as postoperative curative intent (group B and six with sinonasal tumours (group C. Dose prescription was at Planning Target Volumes (PTV with simultaneous integrated boost: 54.45Gy and 69.96Gy in 33 fractions (group A; 54.45Gy and 66Gy in 33 fractions (group B and 55Gy in 25 fractions (group C. Results Concerning planning optimization strategies and constraints, as per PTV coverage, for all groups, D98% > 95% and V95% > 99%. As regards organs at risk, all planning objectives were respected, and this was correlated with observed acute toxicity rates. Only 28% of patients experienced G3 mucositis, 14% G3 dermitis 44% had G2 dysphagia. Nobody required feeding tubes to be placed during treatment. Acute toxicity is also related to chemotherapy. Two patients interrupted the course of radiotherapy because of a quick worsening of general clinical condition. Conclusions These preliminary results stated that volumetric modulated arc therapy in locally advanced head and neck cancers is feasible and effective, with acceptable toxicities.

  14. Modulation of early and late event-related potentials by emotion

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    Sarah J. Hart

    2012-11-01

    Full Text Available Although emotionally salient stimuli influence higher order information processing, the relative vulnerability of specific stages of cognitive processing to modulation by emotional input remains elusive. To test the temporal dynamics of emotional interference during executive function, we recorded event-related potentials while participants performed an effortful anticipation task with aversive emotional and neutral distracters. Participants were presented with a modified delayed Stroop task that dissociated the anticipation of an easier or more difficult task (instructional cues to attend to word versus color from the response to the Stroop stimulus, while aversive and neutral pictures were displayed during the delay period. Our results indicated a relative decrease in the amplitude of the contingent negative variation (CNV during aversive trials that was greater during the early anticipatory phase than during the later response preparation phase, and greater during (the more difficult color than word trials. During the initial stage of cue processing, there was also significant interaction between emotion and anticipatory difficulty on N1 amplitude, where emotional stimuli led to significantly enhanced negativity during color cues relative to word cues. These results suggest that earlier processes of orientation and effortful anticipation may reflect executive engagement that is influenced by emotional interference while later phases of response preparation may be modulated by emotional interference regardless of anticipatory difficulty.

  15. Carotid body oxygen sensing and adaptation to hypoxia.

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

    2016-01-01

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

  16. Musical training modulates the early but not the late stage of rhythmic syntactic processing.

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    Sun, Lijun; Liu, Fang; Zhou, Linshu; Jiang, Cunmei

    2017-08-23

    Syntactic processing is essential for musical understanding. Although the processing of harmonic syntax has been well studied, very little is known about the neural mechanisms underlying rhythmic syntactic processing. The present study investigated the neural processing of rhythmic syntax and whether and to what extent long-term musical training impacts such processing. Fourteen musicians and 14 nonmusicians listened to syntactic-regular or syntactic-irregular rhythmic sequences and judged the completeness of these sequences. Nonmusicians, as well as musicians, showed a P600 effect to syntactic-irregular endings, indicating that musical exposure and perceptual learning of music are sufficient to enable nonmusicians to process rhythmic syntax at the late stage. However, musicians, but not nonmusicians, also exhibited an early right anterior negativity (ERAN) response to syntactic-irregular endings, which suggests that musical training only modulates the early but not the late stage of rhythmic syntactic processing. These findings revealed for the first time the neural mechanisms underlying the processing of rhythmic syntax in music, which has important implications for theories of hierarchically organized music cognition and comparative studies of syntactic processing in music and language. © 2017 Society for Psychophysiological Research.

  17. Modulation of early stress-induced neurobiological changes: a review of behavioural and pharmacological interventions in animal models

    OpenAIRE

    Harrison, E L; Baune, B T

    2014-01-01

    Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher incidence of treatment resistance compared with individuals with no such history. Modulation of the influence early stress exerts over neurobiology may help to prevent the development of psychiatric disorders in some cases, while attenuating the extent of treatment resistance in those with established psychiatric disorders. T...

  18. Carotid sparing intensity modulated radiotherapy on early glottic cancer: Preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hoon Sik; Jeong, Bae Kwon; Jeong, Ho Jin; Song, Jin Ho; Kim, Jin Pyeong; Park, Jung Je; Woo, Seung Hoon; Kang, Ki Mun [Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju (Korea, Republic of)

    2016-03-15

    To compare the dose distribution between carotid sparing intensity modulated radiotherapy (IMRT) and opposed lateral field technique (LAFT), and to determine the effects of carotid sparing IMRT in early glottic cancer patients who have risk factors for atherosclerosis. Ten early glottic cancer patients were treated with carotid sparing IMRT. For each patient, the conventional LAFT plan was developed for comparison. IMRT and LAFT plans were compared in terms of planning target volume (PTV) coverage, conformity index, homogeneity index, and the doses to planning organ at risk volume (PRV) for carotid arteries, spinal cord and pharyngeal constrictor muscle. Recurrence was not observed in any patients during the follow-up period. V95% for PTV showed no significant difference between IMRT and LAFT plans, while V100% was significantly higher in the IMRT plan (95.5% vs. 94.6%, p = 0.005). The homogeneity index (11.6%) and conformity index (1.4) in the IMRT plan were significantly better than those in the LAFT plans (8.5% and 5.1, respectively) (p = 0.005). The median V5Gy (90.0%), V25Gy (13.5%), and V50Gy (0%) for carotid artery PRV in the IMRT plan were significantly lower than those in the LAFT plan (99.1%, 89.0%, and 77.3%, respectively) (p = 0.005). Our study suggests that carotid sparing IMRT can significantly decrease the dose to carotid arteries compared to LAFT, and it would be considered for early glottic cancer patient with high risk of atherosclerosis.

  19. Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis.

    Science.gov (United States)

    Gautier-Veyret, Elodie; Arnaud, Claire; Bäck, Magnus; Pépin, Jean-Louis; Petri, Marcelo H; Baguet, Jean-Philippe; Tamisier, Renaud; Lévy, Patrick; Stanke-Labesque, Françoise

    2013-08-01

    Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, pintermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

  20. Modulation of early stress-induced neurobiological changes: a review of behavioural and pharmacological interventions in animal models.

    Science.gov (United States)

    Harrison, E L; Baune, B T

    2014-05-13

    Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher incidence of treatment resistance compared with individuals with no such history. Modulation of the influence early stress exerts over neurobiology may help to prevent the development of psychiatric disorders in some cases, while attenuating the extent of treatment resistance in those with established psychiatric disorders. This review aims to critically evaluate the ability of behavioural, environmental and pharmacologic interventions to modulate neurobiological changes induced by early stress in animal models. Databases were systematically searched to locate literature relevant to this review. Early adversity was defined as stress that resulted from manipulation of the mother-infant relationship. Analysis was restricted to animal models to enable characterisation of how a given intervention altered specific neurobiological changes induced by early stress. A wide variety of changes in neurobiology due to early stress are amenable to intervention. Behavioural interventions in childhood, exercise in adolescence and administration of epigenetic-modifying drugs throughout life appear to best modulate cellar and behavioural alterations induced by childhood adversity. Other pharmacotherapies, such as endocannabinoid system modulators, anti-inflammatories and antidepressants can also influence these neurobiological and behavioural changes that result from early stress, although findings are less consistent at present and require further investigation. Further work is required to examine the influence that behavioural interventions, exercise and epigenetic-modifying drugs exert over alterations that occur following childhood stress in human studies, before possible translational into clinical practice is possible.

  1. Phase noise reveals early category-specific modulation of the event-related potentials.

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    Németh, Kornél; Kovács, Petra; Vakli, Pál; Kovács, Gyula; Zimmer, Márta

    2014-01-01

    Previous studies have found that the amplitude of the early event-related potential (ERP) components evoked by faces, such as N170 and P2, changes systematically as a function of noise added to the stimuli. This change has been linked to an increased perceptual processing demand and to enhanced difficulty in perceptual decision making about faces. However, to date it has not yet been tested whether noise manipulation affects the neural correlates of decisions about face and non-face stimuli similarly. To this end, we measured the ERPs for faces and cars at three different phase noise levels. Subjects performed the same two-alternative age-discrimination task on stimuli chosen from young-old morphing continua that were created from faces as well as cars and were calibrated to lead to similar performances at each noise-level. Adding phase noise to the stimuli reduced performance and enhanced response latency for the two categories to the same extent. Parallel to that, phase noise reduced the amplitude and prolonged the latency of the face-specific N170 component. The amplitude of the P1 showed category-specific noise dependence: it was enhanced over the right hemisphere for cars and over the left hemisphere for faces as a result of adding phase noise to the stimuli, but remained stable across noise levels for cars over the left and for faces over the right hemisphere. Moreover, noise modulation altered the category-selectivity of the N170, while the P2 ERP component, typically associated with task decision difficulty, was larger for the more noisy stimuli regardless of stimulus category. Our results suggest that the category-specificity of noise-induced modulations of ERP responses starts at around 100 ms post-stimulus.

  2. The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

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    Mehtap Kilic Eren

    Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

  3. Modulation of RAB5A early endosome trafficking in response to KRas mediated macropinocytic fluxes in pancreatic cancer cells.

    Science.gov (United States)

    Teske, Christian; Schweitzer, Christine; Palamidessi, Andrea; Aust, Daniela E; Scita, Giorgio; Weitz, Jürgen; Welsch, Thilo

    2017-09-01

    KRAS is the key mutated gene in pancreatic ductal adenocarcinoma (PDAC). Emerging evidence indicates that KRas modulates endocytic uptake. The present study aimed to explore the fate of early endosomal trafficking under the control of KRas expression in PDAC. Surprisingly, PANC-1 cells lacking KRas exhibited significantly enlarged early and late endosomes containing internalized dextran and epidermal growth factor. Endosome enlargement was accompanied by reduced endosomal degradation. Both KRas silencing and lysosomal blockade caused an upregulation of the master regulator of early endosome biogenesis, RAB5A, which is likely responsible for the expansion of the early endosomal compartment, because simultaneous KRAS/RAB5A knockdown abolished endosome enlargement. In contrast, early endosome shrinkage was seen in MIA PaCa-2 cells despite RAB5A upregulation, indicating that distinct KRas-modulated responses operate in different metabolic subtypes of PDAC. In conclusion, mutant KRAS promotes endosomal degradation in PDAC cell lines, which is impaired by KRAS silencing. Moreover, KRAS silencing activates RAB5A upregulation and drives PDAC subtype-dependent modulation of endosome trafficking. Copyright © 2017. Published by Elsevier Inc.

  4. Sucrose is an early modulator of the key hormonal mechanisms controlling bud outgrowth in Rosa hybrida.

    Science.gov (United States)

    Barbier, François; Péron, Thomas; Lecerf, Marion; Perez-Garcia, Maria-Dolores; Barrière, Quentin; Rolčík, Jakub; Boutet-Mercey, Stéphanie; Citerne, Sylvie; Lemoine, Remi; Porcheron, Benoît; Roman, Hanaé; Leduc, Nathalie; Le Gourrierec, José; Bertheloot, Jessica; Sakr, Soulaiman

    2015-05-01

    Sugar has only recently been identified as a key player in triggering bud outgrowth, while hormonal control of bud outgrowth is already well established. To get a better understanding of sugar control, the present study investigated how sugar availability modulates the hormonal network during bud outgrowth in Rosa hybrida. Other plant models, for which mutants are available, were used when necessary. Buds were grown in vitro to manipulate available sugars. The temporal patterns of the hormonal regulatory network were assessed in parallel with bud outgrowth dynamics. Sucrose determined bud entrance into sustained growth in a concentration-dependent manner. Sustained growth was accompanied by sustained auxin production in buds, and sustained auxin export in a DR5::GUS-expressing pea line. Several events occurred ahead of sucrose-stimulated bud outgrowth. Sucrose upregulated early auxin synthesis genes (RhTAR1, RhYUC1) and the auxin efflux carrier gene RhPIN1, and promoted PIN1 abundance at the plasma membrane in a pPIN1::PIN1-GFP-expressing tomato line. Sucrose downregulated both RwMAX2, involved in the strigolactone-transduction pathway, and RhBRC1, a repressor of branching, at an early stage. The presence of sucrose also increased stem cytokinin content, but sucrose-promoted bud outgrowth was not related to that pathway. In these processes, several non-metabolizable sucrose analogues induced sustained bud outgrowth in R. hybrida, Pisum sativum, and Arabidopsis thaliana, suggesting that sucrose was involved in a signalling pathway. In conclusion, we identified potential hormonal candidates for bud outgrowth control by sugar. They are central to future investigations aimed at disentangling the processes that underlie regulation of bud outgrowth by sugar.

  5. Local tissue hypoxia and formation of nasal polyps

    Institute of Scientific and Technical Information of China (English)

    姜舒; 董震; 朱冬冬; 杨占泉

    2003-01-01

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

  6. Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter.

    Science.gov (United States)

    Kraus, Richard J; Yu, Xianming; Cordes, Blue-Leaf A; Sathiamoorthi, Saraniya; Iempridee, Tawin; Nawandar, Dhananjay M; Ma, Shidong; Romero-Masters, James C; McChesney, Kyle G; Lin, Zhen; Makielski, Kathleen R; Lee, Denis L; Lambert, Paul F; Johannsen, Eric C; Kenney, Shannon C; Mertz, Janet E

    2017-06-01

    When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic

  7. Cyclooxygenase-2 suppresses hypoxia-induced apoptosis via a combination of direct and indirect inhibition of p53 activity in a human prostate cancer cell line.

    Science.gov (United States)

    Liu, Xin-Hua; Kirschenbaum, Alexander; Yu, Kang; Yao, Shen; Levine, Alice C

    2005-02-04

    Although p53-inactivating mutations have been described in the majority of human cancers, their role in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is activated by hypoxia and other stressors and is primarily regulated by the Mdm2 protein. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and other eicosanoids, is also induced by hypoxia. COX-2 and resultant prostaglandins increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2-negative MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was compared in COX-2+ versus COX-2- cells under normoxic and hypoxic conditions. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2-expressing cells exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity, and this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrated a role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and indirect modulation of Mdm2 activity. These data imply that COX-2-positive prostate cancer cells can have impaired p53 function even in the presence of wild-type p53 and that p53

  8. Early Visual Cortex Dynamics during Top-Down Modulated Shifts of Feature-Selective Attention.

    Science.gov (United States)

    Müller, Matthias M; Trautmann, Mireille; Keitel, Christian

    2016-04-01

    Shifting attention from one color to another color or from color to another feature dimension such as shape or orientation is imperative when searching for a certain object in a cluttered scene. Most attention models that emphasize feature-based selection implicitly assume that all shifts in feature-selective attention underlie identical temporal dynamics. Here, we recorded time courses of behavioral data and steady-state visual evoked potentials (SSVEPs), an objective electrophysiological measure of neural dynamics in early visual cortex to investigate temporal dynamics when participants shifted attention from color or orientation toward color or orientation, respectively. SSVEPs were elicited by four random dot kinematograms that flickered at different frequencies. Each random dot kinematogram was composed of dashes that uniquely combined two features from the dimensions color (red or blue) and orientation (slash or backslash). Participants were cued to attend to one feature (such as color or orientation) and respond to coherent motion targets of the to-be-attended feature. We found that shifts toward color occurred earlier after the shifting cue compared with shifts toward orientation, regardless of the original feature (i.e., color or orientation). This was paralleled in SSVEP amplitude modulations as well as in the time course of behavioral data. Overall, our results suggest different neural dynamics during shifts of attention from color and orientation and the respective shifting destinations, namely, either toward color or toward orientation.

  9. Investigating emotional top down modulation of ambiguous faces by single pulse TMS on early visual cortices

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    Zachary Adam Yaple

    2016-06-01

    Full Text Available Top-down processing is a mechanism in which memory, context and expectation are used to perceive stimuli. For this study we investigated how emotion content, induced by music mood, influences perception of happy and sad emoticons. Using single pulse TMS we stimulated right occipital face area (rOFA, primary visual cortex (V1 and vertex while subjects performed a face-detection task and listened to happy and sad music. At baseline, incongruent audio-visual pairings decreased performance, demonstrating dependence of emotion while perceiving ambiguous faces. However, performance of face identification decreased during rOFA stimulation regardless of emotional content. No effects were found between Cz and V1 stimulation. These results suggest that while rOFA is important for processing faces regardless of emotion, V1 stimulation had no effect. Our findings suggest that early visual cortex activity may not integrate emotional auditory information with visual information during emotion top-down modulation of faces.

  10. Pneumonia, Acute Respiratory Distress Syndrome, and Early Immune-Modulator Therapy

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    Kyung-Yil Lee

    2017-02-01

    Full Text Available Acute respiratory distress syndrome (ARDS is caused by infectious insults, such as pneumonia from various pathogens or related to other noninfectious events. Clinical and histopathologic characteristics are similar across severely affected patients, suggesting that a common mode of immune reaction may be involved in the immunopathogenesis of ARDS. There may be etiologic substances that have an affinity for respiratory cells and induce lung cell injury in cases of ARDS. These substances originate not only from pathogens, but also from injured host cells. At the molecular level, these substances have various sizes and biochemical characteristics, classifying them as protein substances and non-protein substances. Immune cells and immune proteins may recognize and act on these substances, including pathogenic proteins and peptides, depending upon the size and biochemical properties of the substances (this theory is known as the protein-homeostasis-system hypothesis. The severity or chronicity of ARDS depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances. Therefore, treatment with early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin as soon as possible may reduce aberrant immune responses in the potential stage of ARDS.

  11. r.massmov: a GRASS GIS module for landslide runout assessment in early warning monitoring systems

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    Cannata, Massimiliano; Molinari, Monia; Meisina, Claudia

    2013-04-01

    In the last decades, early warning systems have become a precious support in hazard management by helping in reducing the possible damages caused by natural and anthropic hazards. Furthermore, in the last years, thanks to the rapid advances in science and technology a new concept of innovative early warning systems has been developed taking advantage of the decreasing costs of sensors and the wide diffusion and coverage of internet services (WFS, WMS, WPS, SOS, etc.). In this concept, simulation models can play an important role: in fact, by allowing the objective assessment of the location and intensity of a possible disaster, they can provide valuable information to support decision makers in taking timely and appropriate disaster responses. r.massmov is a new GRASS GIS module for landslide runout simulation over complex topographies developed to meet the expectation of innovative early warning systems modeling services, identified by the authors through four key requirements: i) low simulation times, ii) geospatial capabilities, iii) three-dimensional analysis and iv) open source approach. The model, based on the combined use of shallow water equations and rheological formulas, is the result of a series of enhancements to the original Massmov2D code (Begueria et al. 2009) to significantly improve algorithms and computational times. With this work the authors want to illustrate the main characteristics of r.massmov model: the governing equations, the input/output data, the algorithms and the results of the model application on a case study located in Tessin (Switzerland) that highlighted the effectiveness of the changes performed to the original code in terms of time performances. Furthermore, the authors want to present a set of GRASS GIS specific tools for r.massmov (r.massmov.sensitivity, r.massmov.calibration, r.ucode), developed to systematize and simplify model sensitivity analysis and calibration procedures. References: Begueria S, Van Asch T W J, Malet J

  12. Anoxia- and hypoxia-induced expression of LDH-A* in the Amazon Oscar, Astronotus crassipinis

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    Vera Maria Fonseca Almeida-Val

    2011-01-01

    Full Text Available Adaptation or acclimation to hypoxia occurs via the modulation of physiologically relevant genes, such as erythropoietin, transferrin, vascular endothelial growth factor, phosphofructokinase and lactate dehydrogenase A. In the present study, we have cloned, sequenced and examined the modulation of the LDH-A gene after an Amazonian fish species, Astronotus crassipinis (the Oscar, was exposed to hypoxia and anoxia. In earlier studies, we have discovered that adults of this species are extremely tolerant to hypoxia and anoxia, while the juveniles are less tolerant. Exposure of juveniles to acute hypoxia and anoxia resulted in increased LDH-A gene expression in skeletal and cardiac muscles. When exposed to graded hypoxia juveniles show decreased LDH-A expression. In adults, the levels of LDH-A mRNA did not increase in hypoxic or anoxic conditions. Our results demonstrate that, when given time for acclimation, fish at different life-stages are able to respond differently to survive hypoxic episodes.

  13. Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury.

    Science.gov (United States)

    Rosenberger, Christian; Rosen, Seymour; Heyman, Samuel N

    2006-10-01

    The pathogenesis of acute kidney injury (AKI), formally termed acute tubular necrosis, is complex and, phenotypically, may range from functional dysregulation without overt morphological features to literal tubular destruction. Hypoxia results from imbalanced oxygen supply and consumption. Increasing evidence supports the view that regional renal hypoxia occurs in AKI irrespective of the underlying condition, even under circumstances basically believed to reflect 'direct' tubulotoxicity. However, at present, it is remains unclear whether hypoxia per se or, rather, re-oxygenation (possibly through reactive oxygen species) causes AKI. Data regarding renal hypoxia in the clinical situation of AKI are lacking and our current concepts regarding renal oxygenation during acute renal failure are presumptive and largely derived from experimental studies. There is robust experimental evidence that AKI is often associated with altered intrarenal microcirculation and oxygenation. Furthermore, renal parenchymal oxygen deprivation seems to participate in the pathogenesis of experimental AKI, induced by exogenous nephrotoxins (such as contrast media, non-steroidal anti-inflammatory drugs or amphotericin), sepsis, pigment and obstructive nephropathies. Sub-lethal cellular hypoxia engenders adaptational responses through hypoxia-inducible factors (HIF). Forthcoming technologies to modulate the HIF system form a novel potential therapeutic approach for AKI.

  14. 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.

  15. 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.

  16. Intermittent hypoxia and neurorehabilitation.

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

    2015-12-15

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

  17. Volumetric Modulated Arc Radiotherapy for Early Stage Non-Small-Cell Lung Carcinoma: Is It Better Than the Conventional Static Beam Intensity Modulated Radiotherapy?

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    Vincent Wing Cheung Wu

    2014-01-01

    Full Text Available This study compared the performance of volumetric modulated arc therapy (VMAT techniques: single arc volumetric modulated arc therapy (SA-VMAT and double arc volumetric modulated arc therapy (DA-VMAT with the static beam conventional intensity modulated radiotherapy (C-IMRT for non-small-cell lung carcinoma (NSCLC. Twelve stage I and II NSCLC patients were recruited and their planning CT with contoured planning target volume (PTV and organs at risk (OARs was used for planning. Using the same dose constraints and planning objectives, the C-IMRT, SA-VMAT, and DA-VMAT plans were optimized. C-IMRT consisted of 7 static beams, while SA-VMAT and DA-VMAT plans consisted of one and two full gantry rotations, respectively. No significant difference was found among the three techniques in target homogeneity and conformity. Mean lung dose in C-IMRT plan was significantly lower than that in DA-VMAT plan P=0.04. The ability of OAR sparing was similar among the three techniques, with no significant difference in V20, V10, or V5 of normal lungs, spinal cord, and heart. Less MUs were required in SA-VMAT and DA-VMAT. Besides, SA-VMAT required the shortest beam on time among the three techniques. In treatment of early stage NSCLC, no significant dosimetric superiority was shown by the VMAT techniques over C-IMRT and DA-VMAT over SA-VMAT.

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

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    Daniel Verduzco

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

  19. Effect of educational module on knowledge of primary school teachers regarding early symptoms of childhood psychiatric disorders

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    Liza Thankam Daniel

    2013-01-01

    Full Text Available Context: University-based pre-service educational programs do not adequately prepare the teachers to have sufficient knowledge and skill for identifying a wide variety of symptoms related to mental health disorders among children. Aims: To assess the effect of educational module on knowledge of primary school teachers regarding early symptoms of childhood psychiatric disorders. Settings and Design: A pre experimental study on a sample of 35 primary school teachers was done in selected schools of Delhi. Materials and Methods: Self-instructional module on early symptoms of childhood psychiatric disorders (SIM on ESCD was developed. Data was collected by using standardized tools including the structured questionnaire for ′Demographic and selected variables′ and pre-test knowledge questionnaire. The subjects were exposed to SIM on ESCD for a period of 15 days. Knowledge regarding early symptoms of childhood psychiatric disorders was assessed twice, first one being before exposure to module and the next one on 16 th day of exposure to module. Statistical Analysis: Data were analyzed using statistical package STATA 9.0 version. Results: Primary school teachers who have been teaching in government schools had high pre-test knowledge score than that in private sector. There was significant difference in mean knowledge score of primary school teachers before (9.71 and after (15.60 the administration of SIM on ESCD. Younger teachers and those who had less years of teaching experience had more knowledge gain score than those who were older and had more teaching experience. Conclusions: In the absence of adequate pre-service and in-service education of primary school teachers on early symptoms of childhood psychiatric disorders, SIM on ESCD is a highly effective and viable method for improving primary school teachers′ knowledge on early symptoms of childhood psychiatric disorders.

  20. Hypoxia and HIFs in regulating the development of the hematopoietic system

    NARCIS (Netherlands)

    P. Imanirad (Parisa); E.A. Dzierzak (Elaine)

    2013-01-01

    textabstractMany physiologic processes during the early stages of mammalian ontogeny, particularly placental and vascular development, take place in the low oxygen environment of the uterus. Organogenesis is affected by hypoxia inducible factor (HIF) transcription factors that are sensors of hypoxia

  1. Hypoxia-Inducible Factor α and Hif-prolyl Hydroxylase Characterization and Gene Expression in Short-Time Air-Exposed Mytilus galloprovincialis.

    Science.gov (United States)

    Giannetto, Alessia; Maisano, Maria; Cappello, Tiziana; Oliva, Sabrina; Parrino, Vincenzo; Natalotto, Antonino; De Marco, Giuseppe; Barberi, Chiara; Romeo, Orazio; Mauceri, Angela; Fasulo, Salvatore

    2015-12-01

    Aquatic organisms experience environmental hypoxia as a result of eutrophication and naturally occurring tidal cycles. Mytilus galloprovincialis, being an anoxic/hypoxic-tolerant bivalve, provides an excellent model to investigate the molecular mechanisms regulating oxygen sensing. Across the animal kingdom, inadequacy in oxygen supply is signalled predominantly by hypoxia-inducible factors (HIF) and Hif-prolyl hydroxylases (PHD). In this study, hif-α 5'-end and partial phd mRNA sequences from M. galloprovincialis were obtained. Phylogenetic and molecular characterization of both HIF-α and PHD putative proteins showed shared key features with the respective orthologues from animals strongly suggesting their crucial involvement in the highly conserved oxygen sensing pathway. Both transcripts displayed a tissue-specific distribution with prominent expression in gills. Quantitative gene expression analysis of hif-α and phd mRNAs from gills of M. galloprovincialis demonstrated that both these key sensors are transcriptionally modulated by oxygen availability during the short-time air exposure and subsequent re-oxygenation treatments proving that they are critical players of oxygen-sensing mechanisms in mussels. Remarkably, hif-α gene expression showed a prompt and transient response suggesting the precocious implication of this transcription factor in the early phase of the adaptive response to hypoxia in Mytilus. HIF-α and PHD proteins were modulated in a time-dependent manner with trends comparable to mRNA expression patterns, thus suggesting a central role of their transcriptional regulation in the hypoxia tolerance strategies in marine bivalves. These results provide molecular information about the effects of oxygen deficiency and identify hypoxia-responsive biomarker genes in mussels applicable in ecotoxicological studies of natural marine areas.

  2. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice.

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    Antonino Sgroi

    Full Text Available BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. METHODS: We performed 70%-hepatectomy in wild type (WT mice, IL-1ra knock-out (KO mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU incorporation, proliferating cell nuclear antigen (PCNA and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. RESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1 and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. CONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

  3. Evolutionary functions of early social modulation of hypothalamic-pituitary-adrenal axis development in humans.

    Science.gov (United States)

    Flinn, Mark V; Nepomnaschy, Pablo A; Muehlenbein, Michael P; Ponzi, Davide

    2011-06-01

    The hypothalamic-pituitary-adrenal axis (HPAA) is highly responsive to social challenges. Because stress hormones can have negative developmental and health consequences, this presents an evolutionary paradox: Why would natural selection have favored mechanisms that elevate stress hormone levels in response to psychosocial stimuli? Here we review the hypothesis that large brains, an extended childhood and intensive family care in humans are adaptations resulting from selective forces exerted by the increasingly complex and dynamic social and cultural environment that co-evolved with these traits. Variations in the modulation of stress responses mediated by specific HPAA characteristics (e.g., baseline cortisol levels, and changes in cortisol levels in response to challenges) are viewed as phenotypically plastic, ontogenetic responses to specific environmental signals. From this perspective, we discuss relations between physiological stress responses and life history trajectories, particularly the development of social competencies. We present brief summaries of data on hormones, indicators of morbidity and social environments from our long-term, naturalistic studies in both Guatemala and Dominica. Results indicate that difficult family environments and traumatic social events are associated with temporal elevations of cortisol, suppressed reproductive functioning and elevated morbidity. The long-term effects of traumatic early experiences on cortisol profiles are complex and indicate domain-specific effects, with normal recovery from physical stressors, but some heightened response to negative-affect social challenges. We consider these results to be consistent with the hypothesis that developmental programming of the HPAA and other neuroendocrine systems associated with stress responses may facilitate cognitive targeting of salient social challenges in specific environments. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

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    Sung-Min Kim

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

  5. Cortical modulations increase in early sessions with brain-machine interface.

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    Miriam Zacksenhouse

    Full Text Available BACKGROUND: During planning and execution of reaching movements, the activity of cortical motor neurons is modulated by a diversity of motor, sensory, and cognitive signals. Brain-machine interfaces (BMIs extract part of these modulations to directly control artificial actuators. However, cortical modulations that emerge in the novel context of operating the BMI are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Here we analyzed the changes in neuronal modulations that occurred in different cortical motor areas as monkeys learned to use a BMI to control reaching movements. Using spike-train analysis methods we demonstrate that the modulations of the firing-rates of cortical neurons increased abruptly after the monkeys started operating the BMI. Regression analysis revealed that these enhanced modulations were not correlated with the kinematics of the movement. The initial enhancement in firing rate modulations declined gradually with subsequent training in parallel with the improvement in behavioral performance. CONCLUSIONS/SIGNIFICANCE: We conclude that the enhanced modulations are related to computational tasks that are significant especially in novel motor contexts. Although the function and neuronal mechanism of the enhanced cortical modulations are open for further inquiries, we discuss their potential role in processing execution errors and representing corrective or explorative activity. These representations are expected to contribute to the formation of internal models of the external actuator and their decoding may facilitate BMI improvement.

  6. 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

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

    Science.gov (United States)

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

    2014-10-01

    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.

  8. Hypoxia-on-a-chip

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    Busek Mathias

    2016-09-01

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

  9. Acidosis, hypoxia and bone.

    Science.gov (United States)

    Arnett, Timothy R

    2010-11-01

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

  10. Early clinical experience of radiotherapy of prostate cancer with volumetric modulated arc therapy

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    Valli Mariacarla

    2010-06-01

    Full Text Available Abstract Background To report about initial clinical experience in radiation treatment of carcinoma of prostate with volumetric modulated arcs with the RapidArc (RA technology. Methods Forty-five patients with a median age of 72 ± 3, affected by prostate carcinoma (T1c: 22 patients, T2a-b: 17 patients, T3a-b: 6 patients. N0: 43 patients, N1-Nx: 2 patients, all M0, with initial PSA of 10.0 ± 3.0 ng/mL, were treated with RapidArc in a feasibility study. All patients were treated with single arc using 6MV photons. Dose prescription ranged between 76 (7 patients and 78 Gy (38 patients in 2Gy/fraction. Plan quality was assessed by means of Dose Volume Histogram (DVH analysis. Technical parameters of arcs and pre-treatment quality assurance results (Gamma Agreement Index, GAI are reported to describe delivery features. Early toxicity was scored (according to the Common Terminology Criteria of Adverse Effects scale, CTCAE, scale at the end of treatment together with biochemical outcome (PSA. Results From DVH data, target coverage was fulfilling planning objectives: V95% was in average higher than 98% and V107%~0.0% (D2%~104.0% in average. Homogeneity D5%-D95% ranged between 6.2 ± 1.0% to 6.7 ± 1.3%. For rectum, all planning objectives were largely met (e.g. V70Gy = 10.7 ± 5.5% against an objective of 2% = 79.4 ± 1.2Gy against an objective of 80.0Gy. Maximum dose to femurs was D2% = 36.7 ± 5.4Gy against an objective of 47Gy. Monitor Units resulted: MU/Gy = 239 ± 37. Average beam on time was 1.24 ± 0.0 minutes. Pre-treatment GAI resulted in 98.1 ± 1.1%. Clinical data were recorded as PSA at 6 weeks after RT, with median values of 0.4 ± 0.4 ng/mL. Concerning acute toxicity, no patient showed grade 2-3 rectal toxicity; 5/42 (12% patients experienced grade 2 dysuria; 18/41 (44% patients preserved complete or partial erectile function. Conclusion RapidArc proved to be a safe, qualitative and advantageous treatment modality for prostate cancer.

  11. Hypoxia attenuates purinergic P2X receptor-induced inflammatory gene expression in brainstem microglia

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    Smith SMC

    2013-08-01

    Full Text Available Stephanie MC Smith,1,2 Gordon S Mitchell,1,2 Scott A Friedle,3 Christine M Sibigtroth,1 Stéphane Vinit,1 Jyoti J Watters1–31Department of Comparative Biosciences, 2Comparative Biomedical Sciences Training Program, 3Program in Cellular and Molecular Biology, University of Wisconsin, Madison, WI, USAAbstract: Hypoxia and increased extracellular nucleotides are frequently coincident in the brainstem. Extracellular nucleotides are potent modulators of microglial inflammatory gene expression via P2X purinergic receptor activation. Although hypoxia is also known to modulate inflammatory gene expression, little is known about how hypoxia or P2X receptor activation alone affects inflammatory molecule production in brainstem microglia, nor how hypoxia and P2X receptor signaling interact when they occur together. In the study reported here, we investigated the ability of a brief episode of hypoxia (2 hours in the presence and absence of the nonselective P2X receptor agonist 2′(3′-O-(4-benzoylbenzoyladenosine-5′-triphosphate (BzATP to promote inflammatory gene expression in brainstem microglia in adult rats. We evaluated inducible nitric oxide synthase (iNOS, tumor necrosis factor alpha (TNFα, and interleukin (IL-6 messenger RNA levels in immunomagnetically isolated brainstem microglia. While iNOS and IL-6 gene expression increased with hypoxia and BzATP alone, TNFα expression was unaffected. Surprisingly, BzATP-induced inflammatory effects were lost after hypoxia, suggesting that hypoxia impairs proinflammatory P2X-receptor signaling. We also evaluated the expression of key P2X receptors activated by BzATP, namely P2X1, P2X4, and P2X7. While hypoxia did not alter their expression, BzATP upregulated P2X4 and P2X7 mRNAs; these effects were ablated in hypoxia. Although both P2X4 and P2X7 receptor expression correlated with increased microglial iNOS and IL-6 levels in microglia from normoxic rats, in hypoxia, P2X7 only correlated with IL-6, and P2X

  12. Early malnutrition, but not age, modulates in the rat the L-Arginine facilitating effect on cortical spreading depression.

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    Frazão, Marília Ferreira; Silva de Seixas Maia, Luciana Maria; Guedes, Rubem Carlos Araújo

    2008-12-05

    Nutritional factors acting during brain development can permanently alter brain electrophysiology. L-Arginine is the precursor of nitric oxide synthesis, which can modulate brain function. Here we investigated the effect of early-in-life administration (during postnatal days 7-28) of L-Arginine (300 mg/(kg day)) on cortical spreading depression (CSD), recorded in well-nourished and malnourished (large litters technique) rats aged 30-40 days (young) and 90-110 days (adult). Compared to water-treated controls, well-nourished L-Arginine-treated rats, but not the malnourished ones, displayed higher CSD velocities (Pbrain weights. It is concluded that early L-Arginine treatment long lastingly increased brain CSD-susceptibility and this effect is abolished by early malnutrition.

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

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

    2012-03-01

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

  14. Sesamin modulation of lipid class and fatty acid profile in early juvenile teleost, Lates calcarifer, fed different dietary oils.

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    Alhazzaa, Ramez; Bridle, Andrew R; Carter, Chris G; Nichols, Peter D

    2012-10-15

    Sesamin, a major sesame seed lignan, has diverse biological functions including the modulation of molecular actions in lipid metabolic pathways and reducing cholesterol levels. Vertebrates have different capacities to biosynthesize long-chain PUFA from dietary precursors and sesamin can enhance the biosynthesis of ALA to EPA and DHA in marine teleost. Early juvenile barramundi, Lates calcarifer, were fed for two weeks on diets rich in ALA or SDA derived from linseed or Echium plantagineum, respectively. Both diets contained phytosterols and less cholesterol compared with a standard fish oil-based diet. The growth rates were reduced in the animals receiving sesamin regardless of the dietary oil. However, the relative levels of n-3 LC-PUFA in total lipid, but not the phospholipid, increased in the whole body by up to 25% in animals fed on sesamin with ALA or SDA. Sesamin reduced the relative levels of triacylglycerols and increased polar lipid, and did not affect the relative composition of phospholipid subclasses or sterols. Sesamin is a potent modulator for LC-PUFA biosynthesis in animals, but probably will have more effective impact at advanced ages. By modulating certain lipid metabolic pathways, sesamin has probably disrupted the body growth and development of organs and tissues in early juvenile barramundi.

  15. Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans.

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    Audrey Bellier

    2009-12-01

    Full Text Available Pore-forming toxins (PFTs are by far the most abundant bacterial protein toxins and are important for the virulence of many important pathogens. As such, cellular responses to PFTs critically modulate host-pathogen interactions. Although many cellular responses to PFTs have been recorded, little is understood about their relevance to pathological or defensive outcomes. To shed light on this important question, we have turned to the only genetic system for studying PFT-host interactions-Caenorhabditis elegans intoxication by Crystal (Cry protein PFTs. We mutagenized and screened for C. elegans mutants resistant to a Cry PFT and recovered one mutant. Complementation, sequencing, transgenic rescue, and RNA interference data demonstrate that this mutant eliminates a gene normally involved in repression of the hypoxia (low oxygen response pathway. We find that up-regulation of the C. elegans hypoxia pathway via the inactivation of three different genes that normally repress the pathway results in animals resistant to Cry PFTs. Conversely, mutation in the central activator of the hypoxia response, HIF-1, suppresses this resistance and can result in animals defective in PFT defenses. These results extend to a PFT that attacks mammals since up-regulation of the hypoxia pathway confers resistance to Vibrio cholerae cytolysin (VCC, whereas down-regulation confers hypersusceptibility. The hypoxia PFT defense pathway acts cell autonomously to protect the cells directly under attack and is different from other hypoxia pathway stress responses. Two of the downstream effectors of this pathway include the nuclear receptor nhr-57 and the unfolded protein response. In addition, the hypoxia pathway itself is induced by PFT, and low oxygen is protective against PFT intoxication. These results demonstrate that hypoxia and induction of the hypoxia response protect cells against PFTs, and that the cellular environment can be modulated via the hypoxia pathway to

  16. Early-life stress mediated modulation of adult neurogenesis and behavior

    NARCIS (Netherlands)

    Korosi, A.; Naninck, E.F.G.; Oomen, C.A.; Schouten, M.; Krugers, H.; Fitzsimons, C.; Lucassen, P.J.

    2012-01-01

    Early life is a period of unique sensitivity during which experience can confer enduring effects on brain structure and function. During early perinatal life the quality of the surrounding environment and experiences, in particular the parent-child relationship, is associated with emotional and cogn

  17. Early-life stress mediated modulation of adult neurogenesis and behavior

    NARCIS (Netherlands)

    Korosi, A.; Naninck, E.F.G.; Oomen, C.A.; Schouten, M.; Krugers, H.; Fitzsimons, C.; Lucassen, P.J.

    2012-01-01

    Early life is a period of unique sensitivity during which experience can confer enduring effects on brain structure and function. During early perinatal life the quality of the surrounding environment and experiences, in particular the parent-child relationship, is associated with emotional and

  18. Duplication and diversification of the hypoxia-inducible IGFBP-1 gene in zebrafish.

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    Hiroyasu Kamei

    Full Text Available BACKGROUND: Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes. METHODOLOGY/PRINCIPAL FINDINGS: We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1. IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker. CONCLUSIONS/SIGNIFICANCE: These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic

  19. SU-E-T-808: Volumetric Modulated Arc Radiotherapy Vs. Intensity-Modulated Radiotherapy for Early-Stage Nasopharyngeal Carcinoma: A Dosimetric Study

    Energy Technology Data Exchange (ETDEWEB)

    Lu, J-Y; Huang, B-T; Zhang, W-Z [Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China)

    2015-06-15

    Purpose: To compare volumetric modulated arc radiotherapy (VMAT) technique with fixed-gantry intensity-modulated radiotherapy (IMRT) technique for early-stage nasopharyngeal carcinoma. Methods: CT datasets of ten patients with early-stage nasopharyngeal carcinoma were included. Dual-arc VMAT and nine-field IMRT plans were generated for each case, and were then compared in terms of planning-target-volume (PTV) coverage, conformity index (CI) and homogeneity index (HI), as well as organ-at-risk (OAR) sparing, planning time, monitor units (MUs) and delivery time. Results: Compared with the IMRT plans, the VMAT plans provided comparable HI and CI of PTVnx (PTV of primary tumor of nasopharynx), superior CI and inferior HI of PTVnd (PTV of lymph nodes), as well as superior CI and comparable HI of PTV60 (high-risk PTV). The VMAT plans provided better sparing of the spinal cord, oral cavity and normal tissue, but inferior sparing of the brainstem planning OAR volume (PRV), larynx and parotids, as well as comparable sparing of the spinal cord PRV, brainstem, lenses, optic nerves, optic chiasm. Moreover, the average planning time (181.6 ± 36.0 min) for the VMAT plans was 171% more than that of the IMRT plans (68.1 ± 7.6 min). The MUs of the VMAT plans (609 ± 43) were 70% lower than those of the IMRT plans (2071 ± 262), while the average delivery time (2.2 ± 0.1 min) was 66% less than that of the IMRT plans (6.6 ± 0.4 min). Conclusion: Compared with the IMRT technique, the VMAT technique can achieve similar or slightly superior target dose distribution, with no significant advantages on OAR sparing, and it can achieve significant reductions of MUs and delivery time.

  20. Early modality-specific somatosensory cortical regions are modulated by attended visual stimuli: interaction of vision, touch and behavioral intent.

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    W. Richard Staines

    2014-04-01

    Full Text Available Bimodal interactions between relevant visual and tactile inputs can facilitate attentional modulation at early stages in somatosensory cortices to achieve goal-oriented behaviors. However, the specific contribution of each sensory system during attentional processing and, importantly, how these interact with the required behavioural motor goals remains unclear. Here we used EEG and event-related potentials (ERPs to test the hypothesis that activity from modality-specific somatosensory cortical regions would be enhanced with task-relevant bimodal (visual-tactile stimuli and that the degree of modulation would depend on the difficulty of the associated sensory-motor task demands. Tactile stimuli were discrete vibrations to the index finger and visual stimuli were horizontal bars on a computer screen, both with random amplitudes. Streams of unimodal (tactile and crossmodal (visual and tactile stimuli were randomly presented and participants were instructed to attend to one type of stimulus (unimodal or crossmodal and responses involved either an indication of the presence of an attended stimulus (detect, or the integration and summation of 2 stimulus amplitudes using a pressure-sensitive ball (grade. Force-amplitude associations were learned in a training session, and no feedback was provided during the task. ERPs were time-locked to tactile stimuli and extracted for early modality-specific components (P50, P100, N140. The P50 was enhanced with bimodal (visual-tactile stimuli that were attended to. This was maximal when the motor requirements involved integration of the 2 stimuli in the grade task and when the visual stimulus occurred before (100 ms the tactile stimulus. These results suggest that visual information relevant for movement modulates early somatosensory processing and that the motor behavioral context influences this likely through interaction of top-down attentional and motor preparatory systems with more bottom-up crossmodal

  1. Hypoxia: A Master Regulator of MicroRNA Biogenesis and Activity

    Science.gov (United States)

    Nallamshetty, Shriram; Chan, Stephen Y.; Loscalzo, Joseph

    2013-01-01

    Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins in order to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short non-coding RNAs that regulate gene expression through post-transcriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor (HIF) are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated order to integrate into the complex hierarchical regulatory network induced by hypoxia. PMID:23712003

  2. Susceptibility of dogs with heartworm disease to hypoxia.

    Science.gov (United States)

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

    1977-09-01

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

  3. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity.

    Science.gov (United States)

    Winning, Sandra; Fandrey, Joachim

    2016-01-01

    Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

  4. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

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    Sandra Winning

    2016-01-01

    Full Text Available Dendritic cells (DCs are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate immunity.

  5. Hypoxia adaptation and hemoglobin mutation in Tibetan chick embryo

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  7. ATF-1 is a hypoxia-responsive transcriptional activator of skeletal muscle mitochondrial-uncoupling protein 3.

    Science.gov (United States)

    Lu, Zhongping; Sack, Michael N

    2008-08-22

    Hypoxia induces oxidative damage in skeletal muscle. Uncoupling protein 3 (UCP3) is the skeletal muscle enriched uncoupling protein and has previously been shown to confer resistance against oxidative stress. We show that hypoxia robustly up-regulates skeletal muscle UCP3 and that the absence of UCP3 in primary skeletal myocytes exacerbates hypoxia-induced reactive oxygen species generation. In this context, we reasoned that the investigation of the regulation of UCP3 may identify novel hypoxia-responsive regulatory pathways that modulate intrinsic anti-oxidant defenses. By screening a transcription factor array of 704 full-length cDNAs in murine C2C12 myoblasts following cotransfection of a murine UCP3 promoter-luciferase construct and myoD we identified numerous candidate regulatory factors that up-regulate UCP3. Active transcription factor-1 (ATF-1) was identified, and as this transcription factor is a known component of a multiprotein hypoxia-induced regulatory complex, we explored its role in hypoxia-mediated UCP3 up-regulation. Site-directed mutagenesis and chromatin immunoprecipitation assays identify a 10-bp region required for ATF-1 induction of UCP3 promoter activity. Hypoxia promotes the phosphorylation of ATF-1, and the knockdown of ATF-1 by shRNA prevents hypoxia-mediated up-regulation of UCP3. Pharmacologic inhibition of p38 MAP kinase prevents both hypoxia-mediated ATF-1 phosphorylation and UCP3 up-regulation. PKA signaling does not modulate hypoxia-induced UCP3 up-regulation and neither does HIF-1alpha activation by cobalt chloride. In conclusion, ATF-1, via p38 MAP kinase activation, functions as a novel regulatory pathway driving UCP3 expression. These data reinforce the role of ATF-1 as a hypoxia-responsive trans-activator and identifies a novel regulatory program that may modulate cellular responses to oxygen-deficit.

  8. Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer’s disease

    NARCIS (Netherlands)

    Lesuis, S.L.; Maurin, H.; Borghgraef, P.; Lucassen, P.J.; Van Leuven, F.; Krugers, H.J.

    2016-01-01

    Stress has been implicated as a risk factor for the severity and progression of sporadic Alzheimer's disease (AD). Early life experiences determine stress responsivity in later life, and modulate age-dependent cognitive decline. Therefore, we examined whether early life experiences influence AD

  9. Instruction via Web-Based Modules in Early Childhood Personnel Preparation: A Mixed-Methods Study of Effectiveness and Learner Perspectives

    Science.gov (United States)

    Hollingsworth, Heidi L.; Lim, Chih-Ing

    2015-01-01

    Effective personnel preparation is critical to the development of a high quality early childhood workforce that provides optimal care and education for young children. This mixed-methods study examined the effectiveness of, and learner perspectives on, instruction via web-based modules within face-to-face early childhood personnel preparation…

  10. Hypoxia, Oxidative Stress and Fat

    Directory of Open Access Journals (Sweden)

    Nikolaus Netzer

    2015-06-01

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

  11. How does a neuron know to modulate its epigenetic machinery in response to early-life environment/experience?

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    Carley A Karsten

    2013-08-01

    Full Text Available Exciting information is emerging about epigenetic mechanisms and their role in long-lasting changes of neuronal gene expression. Whereas these mechanisms are active throughout life, recent findings point to a critical window of early postnatal development during which neuronal gene expression may be persistently re-programmed via epigenetic modifications. However, it remains unclear how the epigenetic machinery is modulated. Here we focus on an important example of early-life programming: the effect of sensory input from the mother on expression patterns of key stress-related genes in the developing brain. We focus on the lasting effects of this early life experience on corticotropin releasing hormone (CRH gene expression in the hypothalamus, and describe recent work that integrates organism-wide signals with cellular signals that in turn impact epigenetic regulation. We describe the operational brain networks that convey sensory input to CRH-expressing cells, and highlight the resulting re-wiring of synaptic connectivity to these neurons. We then move from intercellular to intracellular mechanisms, speculating about the induction and maintenance of lifelong CRH repression provoked by early-life experience. Elucidating such pathways is critical for understanding the enduring links between experience and gene expression. In the context of responses to stress, such mechanisms should contribute to vulnerability or resilience to post-traumatic stress disorder (PTSD and other stress-related disorders.

  12. Large-scale transcriptional response to hypoxia in Aspergillus fumigatus observed using RNAseq identifies a novel hypoxia regulated ncRNA.

    Science.gov (United States)

    Losada, Liliana; Barker, Bridget M; Pakala, Suman; Pakala, Suchitra; Joardar, Vinita; Zafar, Nikhat; Mounaud, Stephanie; Fedorova, Natalie; Nierman, William C; Cramer, Robert A

    2014-12-01

    We utilized RNAseq analysis of the Aspergillus fumigatus response to early hypoxic condition exposure. The results show that more than 89% of the A. fumigatus genome is expressed under normoxic and hypoxic conditions. Replicate samples were highly reproducible; however, comparisons between normoxia and hypoxia revealed that >23 and 35% of genes were differentially expressed after 30 and 120 min of hypoxia exposure, respectively. Consistent with our previous report detailing transcriptomic and proteomic responses at later time points, the results here show major repression of ribosomal function and induction of ergosterol biosynthesis, as well as activation of alternate respiratory mechanisms at the later time point. RNAseq data were used to define 32 hypoxia-specific genes, which were not expressed under normoxic conditions. Transcripts of a C6 transcription factor and a histidine kinase-response regulator were found only in hypoxia. In addition, several genes involved in the phosphoenylpyruvate and D-glyceraldehyde-3-phosphate metabolism were only expressed in hypoxia. Interestingly, a 216-bp ncRNA Afu-182 in the 3' region of insA (AFUB_064770) was significantly repressed under hypoxia with a 40-fold reduction in expression. A detailed analysis of Afu-182 showed similarity with several genes in the genome, many of which were also repressed in hypoxia. The results from this study show that hypoxia induces very early and widely drastic genome-wide responses in A. fumigatus that include expression of protein-coding and ncRNA genes. The role of these ncRNA genes in regulating the fungal hypoxia response is an exciting future research direction.

  13. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

    Science.gov (United States)

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

  14. Hypoxia and hypoxia-inducible factors in leukaemias

    Directory of Open Access Journals (Sweden)

    Margaux eDeynoux

    2016-02-01

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

  15. Hypobaric intermittent hypoxia attenuates hypoxia-induced depressor response.

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    Fang Cui

    Full Text Available BACKGROUND: Hypobaric intermittent hypoxia (HIH produces many favorable effects in the cardiovascular system such as anti-hypertensive effect. In this study, we showed that HIH significantly attenuated a depressor response induced by acute hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley rats received HIH in a hypobaric chamber simulating an altitude of 5000 m. The artery blood pressure (ABP, heart rate (HR and renal sympathetic nerve activity (RSNA were recorded in anesthetized control rats and rats received HIH. The baseline ABP, HR and RSNA were not different between HIH and control rats. Acute hypoxia-induced decrease in ABP was significantly attenuated in HIH rat compared with control rats. However, acute hypoxia-induced increases in HR and RSNA were greater in HIH rat than in control rats. After removal of bilateral ascending depressor nerves, acute hypoxia-induced depressor and sympathoexcitatory responses were comparable in control and HIH rats. Furthermore, acute hypoxia-induced depressor and sympathoexcitatory responses did not differ between control and HIH groups after blocking ATP-dependent K(+ channels by glibenclamide. The baroreflex function evaluated by intravenous injection of phenylephrine and sodium nitroprusside was markedly augmented in HIH rats compared with control rats. The pressor and sympathoexcitatory responses evoked by intravenous injection of cyanide potassium were also significantly greater in HIH rats than in control rats. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that HIH suppresses acute hypoxia-induced depressor response through enhancement of baroreflex and chemoreflex function, which involves activation of ATP-dependent K(+ channels. This study provides new information and underlying mechanism on the beneficiary effect of HIH on maintaining cardiovascular homeostasis.

  16. News about VDAC1 in hypoxia

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    Nathalie M. Mazure

    2016-08-01

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

  17. News about VDAC1 in Hypoxia.

    Science.gov (United States)

    Mazure, N M

    2016-01-01

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

  18. Comparative studies of hemolymph physiology response and HIF-1 expression in different strains of Litopenaeus vannamei under acute hypoxia.

    Science.gov (United States)

    Wei, Lin; Li, Yuhu; Qiu, Liguo; Zhou, Hailong; Han, Qian; Diao, Xiaoping

    2016-06-01

    Litopenaeus vannamei has a high commercial value and is the primary cultured shellfish species globally. In this study, we have compared the hemolymph physiological responses between two L. vannamei strains under acute hypoxia. The results showed that hemocyanin concentration (HC) of strain A6410 was significantly higher than strain Zhengda; Total hemocyte counts (THC) decreased significantly in both strains under hypoxic stress (p 0.05), but in the gills and hepatopancreas under hypoxia for 12 h (p Litopenaeus vannamei was closely correlated with the expression level of HIF-1, and the higher expression level of HIF-1 to hypoxia, the lower tolerance to hypoxia in the early stage of hypoxia. These results can help to better understand the molecular mechanisms of hypoxic tolerance and speed up the selective breeding process of hypoxia tolerance in L. vannamei.

  19. Hypoxia regulates stemness of breast cancer MDA-MB-231 cells.

    Science.gov (United States)

    Xie, Jing; Xiao, Yong; Zhu, Xiao-yan; Ning, Zhou-yu; Xu, Hai-fan; Wu, Hui-min

    2016-05-01

    Human breast cancers include cancer stem cell populations as well as non-tumorigenic cancer cells. Breast cancer stem cells possess self-renewal capability and thus are the root cause of recurrence and metastasis of malignant tumors. Hypoxia is a fundamental pathological feature of solid tumor tissues and exerts a wide range of effects on the biological behavior of cancer cells. However, there is little information on the role of hypoxia in modulating the stemness of breast cancer cells. In the present study, we cultured MDA-MB-231 cells in a hypoxic gas mixture to simulate the hypoxic environment in tissues and to determine how hypoxia conditions could affect the cell proliferation, apoptosis, cytotoxicity, and colony-forming ability. Expression of the stem cell phenotype CD24(-)CD44(+)ESA(+) was analyzed to assess the effects of hypoxia on stemness transformation in MDA-MB-231 cells. Our results found that the cell toxicity of MDA-MB-231 cells was not affected by hypoxia. Hypoxia could slightly inhibit the growth of MDA-MB-231 cells, but the inhibitory effect is not significant when compared with normoxic control. Moreover, hypoxia significantly blocked the apoptosis in MDA-MB-231 cells (P MB-231 cells was increased greatly after they were treated with hypoxia, and cell colony-formation rate of MDA-MB-231 cells also increased significantly in hypoxia-treated cells. These results encourage the exploration of hypoxia as a mechanism which might not be underestimated in chemo-resistant breast cancer treatment.

  20. Comparative dosimetry of volumetric modulated arc therapy and limited-angle static intensity-modulated radiation therapy for early-stage larynx cancer

    Energy Technology Data Exchange (ETDEWEB)

    Riegel, Adam C.; Antone, Jeffrey [Department of Radiation Medicine, North Shore–LIJ Health System, New Hyde, Park, NY (United States); Schwartz, David L., E-mail: dschwartz3@nshs.edu [Department of Radiation Medicine, North Shore–LIJ Health System, New Hyde, Park, NY (United States); Hofstra–NSLIJ School of Medicine, Hempstead, NY (United States)

    2013-04-01

    To compare relative carotid and normal tissue sparing using volumetric-modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) for early-stage larynx cancer. Seven treatment plans were retrospectively created on 2 commercial treatment planning systems for 11 consecutive patients with T1-2N0 larynx cancer. Conventional plans consisted of opposed-wedged fields. IMRT planning used an anterior 3-field beam arrangement. Two VMAT plans were created, a full 360° arc and an anterior 180° arc. Given planning target volume (PTV) coverage of 95% total volume at 95% of 6300 cGy and maximum spinal cord dose below 2500 cGy, mean carotid artery dose was pushed as low as possible for each plan. Deliverability was assessed by comparing measured and planned planar dose with the gamma (γ) index. Full-arc planning provided the most effective carotid sparing but yielded the highest mean normal tissue dose (where normal tissue was defined as all soft tissue minus PTV). Static IMRT produced next-best carotid sparing with lower normal tissue dose. The anterior half-arc produced the highest carotid artery dose, in some cases comparable with conventional opposed fields. On the whole, carotid sparing was inversely related to normal tissue dose sparing. Mean γ indexes were much less than 1, consistent with accurate delivery of planned treatment. Full-arc VMAT yields greater carotid sparing than half-arc VMAT. Limited-angle IMRT remains a reasonable alternative to full-arc VMAT, given its ability to mediate the competing demands of carotid and normal tissue dose constraints. The respective clinical significance of carotid and normal tissue sparing will require prospective evaluation.

  1. Early changes in microbial colonization selectively modulate intestinal enzymes, but not inducible heat shock proteins in young adult Swine.

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    Marie-Edith Arnal

    Full Text Available Metabolic diseases and obesity are developing worldwide in a context of plethoric intake of high energy diets. The intestine may play a pivotal role due to diet-induced alterations in microbiota composition and increased permeability to bacterial lipopolysaccharide inducing metabolic inflammation. Early programming of metabolic disorders appearing in later life is also suspected, but data on the intestine are lacking. Therefore, we hypothesized that early disturbances in microbial colonization have short- and long-lasting consequences on selected intestinal components including key digestive enzymes and protective inducible heat shock proteins (HSP. The hypothesis was tested in swine offspring born to control mothers (n = 12 or mothers treated with the antibiotic amoxicillin around parturition (n = 11, and slaughtered serially at 14, 28 and 42 days of age to assess short-term effects. To evaluate long-term consequences, young adult offspring from the same litters were offered a normal or a fat-enriched diet for 4 weeks between 140 and 169 days of age and were then slaughtered. Amoxicillin treatment transiently modified both mother and offspring microbiota. This was associated with early but transient reduction in ileal alkaline phosphatase, HSP70 (but not HSP27 and crypt depth, suggesting a milder or delayed intestinal response to bacteria in offspring born to antibiotic-treated mothers. More importantly, we disclosed long-term consequences of this treatment on jejunal alkaline phosphatase (reduced and jejunal and ileal dipeptidylpeptidase IV (increased and decreased, respectively of offspring born to antibiotic-treated dams. Significant interactions between early antibiotic treatment and later diet were observed for jejunal alkaline phosphatase and sucrase. By contrast, inducible HSPs were not affected. In conclusion, our data suggest that early changes in bacterial colonization not only modulate intestinal architecture and function transiently

  2. Early milk availability modulates the activity of choline acetyltransferase in the cerebral cortex of rats.

    Science.gov (United States)

    Aizawa, Shu; Nakamura, Ryosuke; Yamaguchi, Yuki; Sensui, Naoto; Yamamuro, Yutaka

    2011-10-01

    The purpose of the present study was to investigate the effect of milk in the early stage of lactation on the maturation of cholinergic neurons in the cerebral cortex of rats. Pups were removed from their mothers immediately following parturition and placed with foster dams at days 5-7 of lactation. At days 18 and 56 after birth, the activity of choline acetyltransferase (ChAT), an enzyme responsible for acetylcholine synthesis, in different areas of the cerebral cortex was examined by high-performance liquid chromatography electrochemical detection. In the frontal and hindlimb/parietal regions of the cerebral cortex, the lack of early milk significantly decreased ChAT activity at days 18 and 56. There was no effect on gains in the body or brain weight of infants. ChAT activity in the occipital area tended to be lower in the early milk-deprived rats. The intake of early milk potentially contributes not only to nutrients for the growth of newborn infants, but also to the functional maturation of the cholinergic neurotransmission system in a region-specific manner.

  3. Plasmacytoid dendritic cell-derived IFNα modulates Th17 differentiation during early Bordetella pertussis infection in mice.

    Science.gov (United States)

    Wu, V; Smith, A A; You, H; Nguyen, T A; Ferguson, R; Taylor, M; Park, J E; Llontop, P; Youngman, K R; Abramson, T

    2016-05-01

    Whooping cough is a highly contagious respiratory disease caused by Bordetella pertussis (B. pertussis). T helper 17 (Th17) cells have a central role in the resolution of the infection. Emerging studies document that type I interferons (IFNs) suppress Th17 differentiation and interleukin (IL)-17 responses in models of infection and chronic inflammation. As plasmacytoid dendritic cells (pDCs) are a major source of type I IFNs, we hypothesize that during B. pertussis infection in mice, pDC-derived IFNα inhibits a rapid increase in Th17 cells. We found that IFNα-secreting pDCs appear in the lungs during the early stages of infection, while a robust rise of Th17 cells in the lungs is detected at 15 days post-infection or later. The presence of IFNα led to reduced Th17 differentiation and proliferation in vitro. Furthermore, in vivo blocking of IFNα produced by pDCs during infection with B. pertussis infection resulted in early increase of Th17 frequency, inflammation, and reduced bacterial loads in the airways of infected mice. Taken together, the experiments reported here describe an inhibitory role for pDCs and pDC-derived IFNα in modulating Th17 responses during the early stages of B. pertussis infection, which may explain the prolonged nature of whooping cough.

  4. Input and output gain modulation by the lateral interhemispheric network in early visual cortex.

    Science.gov (United States)

    Wunderle, Thomas; Eriksson, David; Peiker, Christiane; Schmidt, Kerstin E

    2015-05-20

    Neurons in the cerebral cortex are constantly integrating different types of inputs. Dependent on their origin, these inputs can be modulatory in many ways and, for example, change the neuron's responsiveness, sensitivity, or selectivity. To investigate the modulatory role of lateral input from the same level of cortical hierarchy, we recorded in the primary visual cortex of cats while controlling synaptic input from the corresponding contralateral hemisphere by reversible deactivation. Most neurons showed a pronounced decrease in their response to a visual stimulus of different contrasts and orientations. This indicates that the lateral network acts via an unspecific gain-setting mechanism, scaling the output of a neuron. However, the interhemispheric input also changed the contrast sensitivity of many neurons, thereby acting on the input. Such a contrast gain mechanism has important implications because it extends the role of the lateral network from pure response amplification to the modulation of a specific feature. Interestingly, for many neurons, we found a mixture of input and output gain modulation. Based on these findings and the known physiology of callosal connections in the visual system, we developed a simple model of lateral interhemispheric interactions. We conclude that the lateral network can act directly on its target, leading to a sensitivity change of a specific feature, while at the same time it also can act indirectly, leading to an unspecific gain setting. The relative contribution of these direct and indirect network effects determines the outcome for a particular neuron.

  5. The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats.

    Science.gov (United States)

    Caplan, M S; Hedlund, E; Hill, N; MacKendrick, W

    1994-02-01

    Nitric oxide is an endothelium-derived relaxing factor that promotes capillary integrity, inhibits leukocyte adherence and activation, and scavenges oxygen radicals. Because these effects are important in experimental intestinal injury, we studied the role of NO inhibition on hypoxia-induced bowel necrosis in the rat and investigated the interaction between platelet-activating factor (PAF) and NO in this model. Sprague-Dawley rats were treated with either hypoxia, NO synthase inhibition (NG-methyl-L-arginine [LNMA] or NG-nitro-L-arginine methyl ester [L-NAME]), hypoxia+LNMA, hypoxia+LNMA+NO donors, or hypoxia+LNMA+PAF receptor inhibition. Evaluations included blood pressure, superior mesenteric artery blood flow, arterial blood gases, histological intestinal injury, intestinal myeloperoxidase activity, and intestinal PAF activity. We found that hypoxia alone for 90 minutes (10% O2, partial O2 pressure = 45 mm Hg) or LNMA alone had no detrimental effects. However, hypoxia+LNMA together caused hypotension, metabolic acidosis, intestinal injury, increased intestinal myeloperoxidase activity, and elevated intestinal PAF concentrations that were prevented by exogenous L-arginine. Furthermore, the hypotension and intestinal injury was prevented by PAF receptor blockade. We conclude that endogenous NO protects the intestine from hypoxia-induced inflammation and injury, and the balance between local PAF and NO modulates the outcome of hypoxia-stressed intestine.

  6. Oxidative Stress and Hypoxia Contribute to Alzheimer's Disease Pathogenesis: Two Sides of the Same Coin

    Directory of Open Access Journals (Sweden)

    Michela Guglielmotto

    2009-01-01

    Full Text Available While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD, the molecular link between ischemia/hypoxia and amyloid precursor protein (APP processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates β-secretase activity, which involves an early release of ROS and an activation of HIF-1α.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  8. [Hemo- and neurodynamics of the human brain during exposure to moderate hypoxic hypoxia].

    Science.gov (United States)

    Alekseev, D A; Zubarev, A F; Krupina, T N; Iarullin, Kh Kh; Kuznets, E I

    1984-01-01

    Synchronous electro- and rheoencephalography were used to study tolerance to moderate hypoxic hypoxia for 30 min at an altitude of 5000 m without additional oxygen supply. As test subject, men with autonomic-vascular dystonia (29-39 years old), 15 men over 40 (41-56 years old), and 16 essentially healthy controls (23-36 years old) were used. The aged volunteers (41-56 years old) did not differ from the controls with respect to their tolerance to hypoxic hypoxia. The men with early symptoms of hypertonic-type dystonia also showed high tolerance to hypoxic hypoxia. The subjects with hypotonic-type dystonia displayed lower tolerance.

  9. Lung Oxidative Damage by Hypoxia

    Directory of Open Access Journals (Sweden)

    O. F. Araneda

    2012-01-01

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

  10. Lung Oxidative Damage by Hypoxia

    Science.gov (United States)

    Araneda, O. F.; Tuesta, M.

    2012-01-01

    One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described. PMID:22966417

  11. Tracheal remodelling in response to hypoxia

    Science.gov (United States)

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

    2010-01-01

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

  12. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

    Science.gov (United States)

    Perez-Caballero, L; Pérez-Egea, R; Romero-Grimaldi, C; Puigdemont, D; Molet, J; Caso, J-R; Mico, J-A; Pérez, V; Leza, J-C; Berrocoso, E

    2014-05-01

    Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

  13. Hypoxia in the changing marine environment

    Digital Repository Service at National Institute of Oceanography (India)

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

    of ecosystems from tropics to high latitudes. Among the various associated phenomena of ecosystem deterioration, hypoxia can cause serious problems in coastal areas as well as oxygen minimum zones in the open ocean. The negative impacts of hypoxia include...

  14. Early

    Directory of Open Access Journals (Sweden)

    Kamel Abd Elaziz Mohamed

    2014-04-01

    Conclusion: Early PDT is recommended for patients who require prolonged tracheal intubation in the ICU as outcomes like the duration of mechanical ventilation length of ICU stay and hospital stay were significantly shorter in early tracheostomy.

  15. Watch out! Magnetoencephalographic evidence for early modulation of attention orienting by fearful gaze cueing.

    Directory of Open Access Journals (Sweden)

    Fanny Lachat

    Full Text Available Others' gaze and emotional facial expression are important cues for the process of attention orienting. Here, we investigated with magnetoencephalography (MEG whether the combination of averted gaze and fearful expression may elicit a selectively early effect of attention orienting on the brain responses to targets. We used the direction of gaze of centrally presented fearful and happy faces as the spatial attention orienting cue in a Posner-like paradigm where the subjects had to detect a target checkerboard presented at gazed-at (valid trials or non gazed-at (invalid trials locations of the screen. We showed that the combination of averted gaze and fearful expression resulted in a very early attention orienting effect in the form of additional parietal activity between 55 and 70 ms for the valid versus invalid targets following fearful gaze cues. No such effect was obtained for the targets following happy gaze cues. This early cue-target validity effect selective of fearful gaze cues involved the left superior parietal region and the left lateral middle occipital region. These findings provide the first evidence for an effect of attention orienting induced by fearful gaze in the time range of C1. In doing so, they demonstrate the selective impact of combined gaze and fearful expression cues in the process of attention orienting.

  16. Beyond pleasure and arousal: appetitive erotic stimuli modulate electrophysiological brain correlates of early attentional processing.

    Science.gov (United States)

    Kuhr, Benjamin; Schomberg, Jessica; Gruber, Thomas; Quirin, Markus

    2013-03-27

    Previous studies investigating affective reactions to pictures that elicit a specific effect have mainly focused on the dimensions valence and arousal. Using an event-related picture-viewing paradigm in electroencephalography, we investigated whether erotica - that is appetitive, evolutionarily relevant stimuli - have effects on early stages of attentional processing that are distinct from those of other positive and arousing stimuli. Seventeen male students viewed arousing photos of erotic, nude women or pictures of extreme sport scenes, as well as control pictures of attractive, dressed women or daily activities. Erotic pictures differed from extreme sport pictures not only in late but also in early attentional processes, as indicated by event-related potentials appearing from 130 ms after stimulus onset (P1). The findings suggest (a) that the dimension of appetence should be considered in addition to valence and arousal when investigating psychophysiological reactions to affective-motivational stimuli and (b) that early attentional processing as mirrored by the P1 can be influenced by motivational systems.

  17. FDG uptake, a surrogate of tumour hypoxia?

    NARCIS (Netherlands)

    Dierckx, Rudi Andre; de Wiele, Christophe Van

    2008-01-01

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

  18. 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

  19. The sheep conceptus modulates proteome profiles in caruncular endometrium during early pregnancy.

    Science.gov (United States)

    Arianmanesh, Mitra; Fowler, Paul A; Al-Gubory, Kaïs H

    2016-12-01

    The stage-specific expression of functional proteins within the endometrium, and their regulation by conceptus-derived signals, are crucial for conceptus development and successful establishment of pregnancy. Accurate knowledge of endometrium-conceptus interactions is key for the development of effective strategies to improve conceptus implantation rates both following natural conception and/or assisted reproductive technologies. The unilateral pregnant ewe provides a powerful experimental model for the study of endometrial function in the presence or absence of conceptuses during the peri-implantation period. Two-dimensional gel electrophoresis and mass spectrometry-based proteomics were used to compare and identify differentially expressed proteins in caruncular endometrium collected from the gravid uterine horns and the non-gravid uterine horns at the time of conceptus attachment (day 16 of pregnancy) and early post-implantation period (day 20 of pregnancy). Fifty seven protein spots were up-regulated in the gravid horn at day 16 of pregnancy and twenty seven protein spots were up-regulated in the gravid horn at day 20 of pregnancy. Sixteen proteins with different functions such as protein metabolism, cholesterol and ion transport and cell adhesion were identified. In conclusion, the use of the unilaterally pregnant ewe model provides evidence that the early implantation and post-implanting conceptus-derived signals up-regulate caruncle endometrial proteins, including carbonic anhydrase 2 (CA-II) and apolipoprotein A-1 (APOA1) and down-regulate caruncle endometrial proteins, including adenosylhomocysteinase (AHCY) and heat shock 60kDa protein 1 (HSP60). These regulated proteins are likely involved in providing a suitable intra-uterine environment required for conceptus attachment, implantation, early post-implantation development and the successful establishment of pregnancy in sheep.

  20. Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury.

    Science.gov (United States)

    Papa, Simonetta; Caron, Ilaria; Erba, Eugenio; Panini, Nicolò; De Paola, Massimiliano; Mariani, Alessandro; Colombo, Claudio; Ferrari, Raffaele; Pozzer, Diego; Zanier, Elisa R; Pischiutta, Francesca; Lucchetti, Jacopo; Bassi, Andrea; Valentini, Gianluca; Simonutti, Giulio; Rossi, Filippo; Moscatelli, Davide; Forloni, Gianluigi; Veglianese, Pietro

    2016-01-01

    Many efforts have been performed in order to understand the role of recruited macrophages in the progression of spinal cord injury (SCI). Different studies revealed a pleiotropic effect played by these cells associated to distinct phenotypes (M1 and M2), showing a predictable spatial and temporal distribution in the injured site after SCI. Differently, the role of activated microglia in injury progression has been poorly investigated, mainly because of the challenges to target and selectively modulate them in situ. A delivery nanovector tool (poly-ε-caprolactone-based nanoparticles) able to selectively treat/target microglia has been developed and used here to clarify the temporal and spatial involvement of the pro-inflammatory response associated to microglial cells in SCI. We show that a treatment with nanoparticles loaded with minocycline, the latter a well-known anti-inflammatory drug, when administered acutely in a SCI mouse model is able to efficiently modulate the resident microglial cells reducing the pro-inflammatory response, maintaining a pro-regenerative milieu and ameliorating the behavioral outcome up to 63 days post injury. Furthermore, by using this selective delivery tool we demonstrate a mechanistic link between early microglia activation and M1 macrophages recruitment to the injured site via CCL2 chemokine, revealing a detrimental contribution of pro-inflammatory macrophages to injury progression after SCI.

  1. State-dependent modulation of functional connectivity in early blind individuals.

    Science.gov (United States)

    Pelland, Maxime; Orban, Pierre; Dansereau, Christian; Lepore, Franco; Bellec, Pierre; Collignon, Olivier

    2017-02-15

    Resting-state functional connectivity (RSFC) studies have provided strong evidences that visual deprivation influences the brain's functional architecture. In particular, reduced RSFC coupling between occipital (visual) and temporal (auditory) regions has been reliably observed in early blind individuals (EB) at rest. In contrast, task-dependent activation studies have repeatedly demonstrated enhanced co-activation and connectivity of occipital and temporal regions during auditory processing in EB. To investigate this apparent discrepancy, the functional coupling between temporal and occipital networks at rest was directly compared to that of an auditory task in both EB and sighted controls (SC). Functional brain clusters shared across groups and cognitive states (rest and auditory task) were defined. In EBs, we observed higher occipito-temporal correlations in activity during the task than at rest. The reverse pattern was observed in SC. We also observed higher temporal variability of occipito-temporal RSFC in EB suggesting that occipital regions in this population may play the role of a multiple demand system. Our study reveals how the connectivity profile of sighted and early blind people is differentially influenced by their cognitive state, bridging the gap between previous task-dependent and RSFC studies. Our results also highlight how inferring group-differences in functional brain architecture solely based on resting-state acquisition has to be considered with caution.

  2. Breast Fibroblasts Modulate Early Dissemination, Tumorigenesis, and Metastasis through Alteration of Extracellular Matrix Characteristics

    Directory of Open Access Journals (Sweden)

    Nancy Dumont

    2013-03-01

    Full Text Available A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

  3. Immune Regulator MCPIP1 Modulates TET Expression during Early Neocortical Development

    Directory of Open Access Journals (Sweden)

    Huihui Jiang

    2016-09-01

    Full Text Available MCPIP1 is a recently identified immune regulator that plays critical roles in preventing immune disorders, and is also present in the brain. Currently an unresolved question remains as to how MCPIP1 performs its non-immune functions in normal brain development. Here, we report that MCPIP1 is abundant in neural progenitor cells (NPCs and newborn neurons during the early stages of neurogenesis. The suppression of MCPIP1 expression impairs normal neuronal differentiation, cell-cycle exit, and concomitant NPC proliferation. MCPIP1 is important for maintenance of the NPC pool. Notably, we demonstrate that MCPIP1 reduces TET (TET1/TET2/TET3 levels and then decreases 5-hydroxymethylcytosine levels. Furthermore, the MCPIP1 interaction with TETs is involved in neurogenesis and in establishing the proper number of NPCs in vivo. Collectively, our findings not only demonstrate that MCPIP1 plays an important role in early cortical neurogenesis but also reveal an unexpected link between neocortical development, immune regulators, and epigenetic modification.

  4. Early ERP modulation during mood adjectives processing in patients with affective disorders.

    Science.gov (United States)

    Grzybowski, Szczepan J; Wyczesany, Miroslaw

    2016-10-06

    Attentional bias is considered a key feature in mood disorders, and yet little is known of its neural correlates within the early stream of information processing in manic and depressed patients. The study aimed to capture and detail attentional bias during emotional word processing in patients within the first 500ms of stimulus exposition. 28 mood adjectives (14 positive and 14 negative) were used as stimuli. We expected differences in adjective encoding between groups during lexico-semantic analysis based on varying attentional resource allocation. Differences were evidenced within the first 100ms after stimulus onset with higher amplitudes for both patient groups than controls, possibly indicating more automatic attention allocation to stimuli during sensory analysis stages. Between 200-290ms after the words' onset, a specific valence mood-word mismatch was registered which approached significance, with higher responses evoked to negative than positive words in manic patients, and the opposite pattern of activity observed in depressed patients, suggesting cognitive bias based on mood incongruence during the lexico-semantic analysis stage. There was also a lateralized pattern of activity, with higher amplitudes over the right hemisphere posteriorly, and higher over the left frontally in the patient groups, especially in the manic individuals. The study points to attentional bias based on mood incongruence processing during crucial stages of meaning encoding within the early stream of information processing.

  5. Past Occurrences of Hypoxia in the Baltic Sea

    Science.gov (United States)

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

    2007-12-01

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

  6. Physical controls of hypoxia in waters adjacent to the Yangtze Estuary: A numerical modeling study.

    Science.gov (United States)

    Chen, Xiaofeng; Shen, Zhenyao; Li, Yangyang; Yang, Ye

    2015-08-15

    A three-dimensional circulation model (the Environmental Fluid Dynamic Code) was used to examine the role that physical forcing (river discharge, wind speed and direction) plays in controlling hypoxia in waters adjacent to the Yangtze Estuary. The model assumes that the biological consumption of oxygen is constant in both time and space, which allows the role of physical forcing in modulating the oxygen dynamics to be isolated. Despite of the simplicity of this model, the simulation results showed that it can reproduce the observed variability of dissolved oxygen in waters adjacent to the Yangtze Estuary, thereby highlighting the important role of changes in physical forcing in the variation of hypoxia. The scenarios tested revealed appreciable changes in the areal extent of hypoxia as a function of wind speed and wind direction. Interestingly, well-developed hypoxia was insensitive to river discharge.

  7. Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences.

    Directory of Open Access Journals (Sweden)

    Juliana T Maricato

    Full Text Available Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i global DNA- methylation; (ii qPCR array and (iii western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-γ and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection

  8. Mycobacterium leprae phenolglycolipid-1 expressed by engineered M. bovis BCG modulates early interaction with human phagocytes.

    Directory of Open Access Journals (Sweden)

    Guillaume Tabouret

    Full Text Available The species-specific phenolic glycolipid 1 (PGL-1 is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3 for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells.

  9. Are plant endogenous factors like ethylene modulators of the early oxidative stress induced by mercury?

    Directory of Open Access Journals (Sweden)

    M Belén eMontero-Palmero

    2014-08-01

    Full Text Available The induction of oxidative stress is one of the quickest symptoms appearing in plants subjected to metal stress. A transcriptional analysis of the early responses of alfalfa (Medicago sativa seedlings to mercury (Hg; 3 µM for 3, 6 and 24 h showed that up-regulation of genes responding to ethylene were up-regulated, a phytohormone known to mediate in the cellular redox homeostasis. In this mini-review we have compared these quick responses with two other concurrent transcriptomic analysis in Barrel medic (Medicago truncatula and barley (Hordeum vulgare under Hg stress. Besides ethylene, ABA and jasmonate related genes were up-regulated, all of them are endogenous factors known to intervene in oxidative stress responses. The information obtained may target future work to understand the cellular mechanisms triggered by Hg, enabling biotechnological approaches to diminish Hg-induced phytotoxicity.

  10. Phonemic versus allophonic status modulates early brain responses to language sounds: an MEG/ERF study

    DEFF Research Database (Denmark)

    Nielsen, Andreas Højlund; Gebauer, Line; Mcgregor, William

    Objective: An early component of the auditory event-related potential (ERP), the mismatch negativity (MMN/MMNm), has been shown to be sensitive to native versus non-native language sounds (Brandmeyer et al., 2012; Kazanina et al., 2006; Näätänen et al., 1997); i.e. sensitive to phonemic versus...... allophonic sound contrasts. So far this has only been attested between languages. In the present study we wished to investigate this effect within the same language: Does the same sound contrast that is phonemic in one environment, but allophonic in another, elicit different MMNm responses in native......] thus as deviants, respectively. Data were preprocessed using Elekta’s MaxFilter software and SPM8, all statistical analyses were conducted in sensor-space using SPM8. Results: Focusing on the 150-300 ms time period after stimulus onset (typical MMNm time range for language sound contrasts), only...

  11. Modulation of electron transfer kinetics by protein conformational fluctuations during early-stage photosynthesis.

    Science.gov (United States)

    Chaudhury, Srabanti; Cherayil, Binny J

    2007-10-14

    The kinetics of electron transfer during the early stages of the photosynthetic reaction cycle has recently been shown in transient absorption experiments carried out by Wang et al. [Science 316, 747 (2007)] to be strongly influenced by fluctuations in the conformation of the surrounding protein. A model of electron transfer rates in polar solvents developed by Sumi and Marcus using a reaction-diffusion formalism [J. Chem. Phys. 84, 4894 (1986)] was found to be successful in fitting the experimental absorption curves over a roughly 200 ps time interval. The fits were achieved using an empirically determined time-dependent function that described protein conformational relaxation. In the present paper, a microscopic model of this function is suggested, and it is shown that the function can be identified with the dynamic autocorrelation function of intersegment distance fluctuations that occur in a harmonic potential of mean force under the action of fractional Gaussian noise.

  12. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events.

    Science.gov (United States)

    Noble, Linda J; Donovan, Frances; Igarashi, Takuji; Goussev, Staci; Werb, Zena

    2002-09-01

    Inflammation in general and proteinases generated as a result are likely mediators of early secondary pathogenesis after spinal cord injury. We report that matrix metalloproteinase-9 (MMP-9) plays an important role in blood-spinal cord barrier dysfunction, inflammation, and locomotor recovery. MMP-9 was present in the meninges and neurons of the uninjured cord. MMP-9 increased rapidly after a moderate contusion spinal cord injury, reaching a maximum at 24 hr, becoming markedly reduced by 72 hr, and not detectable at 7 d after injury. It was seen in glia, macrophages, neutrophils, and vascular elements in the injured spinal cord at 24 hr after injury. The natural tissue inhibitors of MMPs were unchanged over this time course. MMP-9-null mice exhibited significantly less disruption of the blood-spinal cord barrier, attenuation of neutrophil infiltration, and significant locomotor recovery compared with wild-type mice. Similar findings were observed in mice treated with a hydroxamic acid MMP inhibitor from 3 hr to 3 d after injury, compared with the vehicle controls. Moreover, the area of residual white matter at the lesion epicenter was significantly greater in the inhibitor-treated group. This study provides evidence that MMP-9 plays a key role in abnormal vascular permeability and inflammation within the first 3 d after spinal cord injury, and that blockade of MMPs during this critical period attenuates these vascular events and leads to improved locomotor recovery. Our findings suggest that early inhibition of MMPs may be an efficacious strategy for the spinal cord-injured patient.

  13. Sucrose-induced analgesia during early life modulates adulthood learning and memory formation.

    Science.gov (United States)

    Nuseir, Khawla Q; Alzoubi, Karem H; Alabwaini, Jehad; Khabour, Omar F; Kassab, Manal I

    2015-06-01

    This study is aimed at examining the long-term effects of chronic pain during early life (postnatal day 0 to 8weeks), and intervention using sucrose, on cognitive functions during adulthood in rats. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution or paracetamol was administered for analgesia before the paw prick. Control groups include tactile stimulation to account for handling and touching the paws, and sucrose alone was used. All treatments were started on day one of birth and continued for 8weeks. At the end of the treatments, behavioral studies were conducted to test the spatial learning and memory using radial arm water maze (RAWM), as well as pain threshold via foot-withdrawal response to a hot plate apparatus. Additionally, the hippocampus was dissected, and blood was collected. Levels of neurotrophins (BDNF, IGF-1 and NT-3) and endorphins were assessed using ELISA. The results show that chronic noxious stimulation resulted in comparable foot-withdrawal latency between noxious and tactile groups. On the other hand, pretreatment with sucrose or paracetamol increased pain threshold significantly both in naive rats and noxiously stimulated rats (Psucrose treatment prevented such impairment (PSucrose significantly increased serum levels of endorphin and enkephalin. Chronic pain decreased levels of BDNF in the hippocampus and this decrease was prevented by sucrose and paracetamol treatments. Hippocampal levels of NT-3 and IGF-1 were not affected by any treatment. In conclusion, chronic pain induction during early life induced short memory impairment, and pretreatment with sucrose prevented this impairment via mechanisms that seem to involve BDNF. As evident in the results, sucrose, whether alone or in the presence of pre-noxious stimulation, increases pain threshold in such circumstances; most likely via a mechanism that involves an increase in endogenous opioids.

  14. How do Early Impacts Modulate the Tectonic, Magnetic and Climatic Evolutions of Terrestrial Planets?

    Science.gov (United States)

    Jellinek, M.; Jackson, M. G.; Lenardic, A.; Weller, M. B.

    2015-12-01

    The landmark discovery showing that the 142Nd/144Nd ratio of the accessible modern terrestrial mantle is greater than ordinary-chondrites has remarkable implications for the formation, as well as the geodynamic, magnetic and climatic histories of Earth. If Earth is derived from ordinary chondrite precursors, mass balance requires that a missing reservoir with 142Nd/144Nd lower than ordinary chondrites was isolated from the accessible mantle within 20-30 Myr following accretion. Critically for Earth evolution, this reservoir hosts the equivalent of the modern continents' budget of radioactive heat-producing elements (U, Th and K). If this reservoir was lost to space through mechanical erosion by early impactors, the planet's radiogenic heat generation is 18-45% lower than chondrite-based compositional estimates. Recent geodynamic calculations suggest that this reduced heat production will favor the emergence of Earth-like plate tectonics. However, parameterized thermal history calculations favor a relatively recent transition from mostly Atlantic-sized plates to the current plate tectonic mode characterized predominantly by the subduction of Pacific-sized plates. Such a transition in the style of Earth's plate tectonics is also consistent with a delayed dynamo and an evolving rate of volcanic outgassing that ultimately favors Earth's long-term clement climate. By contrast, relatively enhanced radiogenic heat production related to a less early impact erosion reduces the likelihood of present day plate tectonics: A chondritic Earth has a stronger likelihood to evolve as a Venus-like planet characterized by potentially wild swings in tectonic and climatic regime. Indeed, differences in internal heat production related to varying extents of impact erosion may exert strong control over Earth's climate and explain aspects of the differences among the current climatic regimes of Earth, Venus and Mars.

  15. Inhibitory repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex modulates early affective processing.

    Science.gov (United States)

    Zwanzger, Peter; Steinberg, Christian; Rehbein, Maimu Alissa; Bröckelmann, Ann-Kathrin; Dobel, Christian; Zavorotnyy, Maxim; Domschke, Katharina; Junghöfer, Markus

    2014-11-01

    The dorsolateral prefrontal cortex (dlPFC) has often been suggested as a key modulator of emotional stimulus appraisal and regulation. Therefore, in clinical trials, it is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). In spite of various encouraging reports that demonstrate beneficial effects of rTMS in anxiety disorders, psychophysiological studies exploring the underlying neural mechanisms are sparse. Here we investigated how inhibitory rTMS influences early affective processing when applied over the right dlPFC. Before and after rTMS or sham stimulation, subjects viewed faces with fearful or neutral expressions while whole-head magnetoencephalography (MEG) was recorded. Due to the disrupted functioning of the right dlPFC, visual processing in bilateral parietal, temporal, and occipital areas was amplified starting at around 90 ms after stimulus onset. Moreover, increased fear-specific activation was found in the right TPJ area in a time-interval between 110 and 170 ms. These neurophysiological effects were reflected in slowed reaction times for fearful, but not for neutral faces in a facial expression identification task while there was no such effect on a gender discrimination control task. Our study confirms the specific and important role of the dlPFC in regulation of early emotional attention and encourages future clinical research to use minimal invasive methods such as transcranial magnetic (TMS) or direct current stimulation (tDCS). Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Intensity-modulated radiation therapy for early-stage breast cancer: is it ready for prime time?

    Science.gov (United States)

    Chan, Tabitha Y; Tan, Poh Wee; Tang, Johann I

    2017-01-01

    Whole breast external beam radiotherapy (WBEBRT) is commonly used as an essential arm in the treatment management of women with early-stage breast cancer. Dosimetry planning for conventional WBEBRT typically involves a pair of tangential fields. Advancement in radiation technology and techniques has the potential to improve treatment outcomes with clinically meaningful long-term benefits. However, this advancement must be balanced with safety and improved efficacy. Intensity-modulated radiation therapy (IMRT) is an advanced technique that shows promise in improving the planning process and radiation delivery. Early data on utilizing IMRT for WBEBRT demonstrate more homogenous dose distribution with reduction in organs at risk doses. This translates to toxicities reduction. The two common descriptors for IMRT are forward-planning “fields in field” and inverse planning. Unlike IMRT for other organs, the aim of IMRT for breast planning is to achieve dose homogeneity and not organ conformality. The aim of this paper was to evaluate whether IMRT is ready for prime time based on these three points: 1) workload impact, 2) the clinical impact on the patient’s quality of life, and 3) the appropriateness and applicability to clinical practice.

  17. Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia.

    Science.gov (United States)

    Lefferts, Wesley K; Hughes, William E; White, Corey N; Brutsaert, Tom D; Heffernan, Kevin S

    2016-02-01

    The matching of oxygen supply to neural demand (i.e., neurovascular coupling (NVC)) is an important determinant of cognitive performance. The impact of hypoxia on NVC remains poorly characterized. NVC is partially modulated by nitric oxide (NO), which may initially decrease in hypoxia. This study investigated the effect of acute NO-donor (nitrate) supplementation on NVC and cognitive function in hypoxia. Twenty healthy men participated in this randomized, double-blind, crossover design study. Following normoxic cognitive/NVC testing, participants consumed either nitrate (NIT) or a NIT-depleted placebo (PLA). Participants then underwent 120 min of hypoxia (11.6% ± 0.1% O2) and all cognitive/NVC testing was repeated. NVC was assessed as change in middle cerebral artery (MCA) blood flow during a cognitive task (incongruent Stroop) using transcranial Doppler. Additional computerized cognitive testing was conducted separately to assess memory, executive function, attention, sensorimotor, and social cognition domains. Salivary nitrite significantly increased following supplementation in hypoxia for NIT (+2.6 ± 1.0 arbitrary units (AU)) compared with PLA (+0.2 ± 0.3 AU; p 0.05). MCA flow increased during Stroop similarly in normoxia (PLA +5 ± 6 cm·s(-1), NIT +7 ± 7 cm·s(-1)) and hypoxia (PLA +5 ± 9 cm·s(-1), NIT +6 ± 7 cm·s(-1)) (p 0.05). In conclusion, acute hypoxia resulted in significant reductions in memory concomitant with preservation of executive function, attention, and sensorimotor function. Hypoxia had no effect on NVC. Acute NIT supplementation had no effect on NVC or cognitive performance in hypoxia.

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

    Science.gov (United States)

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

    2016-01-01

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

  19. Neurological damage arising from intrapartum hypoxia/acidosis.

    Science.gov (United States)

    Rei, M; Ayres-de-Campos, D; Bernardes, J

    2016-01-01

    Complications occurring at any level of foetal oxygen supply will result in hypoxaemia, and this may ultimately lead to hypoxia/acidosis and neurological damage. Hypoxic-ischaemic encephalopathy (HIE) is the short-term neurological dysfunction caused by intrapartum hypoxia/acidosis, and this diagnosis requires the presence of a number of findings, including the confirmation of newborn metabolic acidosis, low Apgar scores, early imaging evidence of cerebral oedema and the appearance of clinical signs of neurological dysfunction in the first 48 h of life. Cerebral palsy (CP) consists of a heterogeneous group of nonprogressive movement and posture disorders, frequently accompanied by cognitive and sensory impairments, epilepsy, nutritional deficiencies and secondary musculoskeletal lesions. Although CP is the most common long-term neurological complication associated with intrapartum hypoxia/acidosis, >80% of cases are caused by other phenomena. Data on minor long-term neurological deficits are scarce, but they suggest that less serious intellectual and motor impairments may result from intrapartum hypoxia/acidosis. This chapter focuses on the existing evidence of neurological damage associated with poor foetal oxygenation during labour. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Interlinking of hypoxia and estrogen in thyroid cancer progression.

    Science.gov (United States)

    Rajoria, S; Hanly, E; Nicolini, A; George, A L; Geliebter, J; Shin, E J; Suriano, R; Carpi, A; Tiwari, R K

    2014-01-01

    Estrogen aids in neo-vascularization of various tumors during hypoxic conditions, however the role of estrogen within the hypoxic environment of thyroid cancer is not known. In a series of experimentations, using human thyroid cancer cells, we observed that estrogen and hypoxia modulate the hypoxia inducible factor-1 (HIF-1) signaling which is abrogated by the anti-estrogen fulvestrant and the HIF-1 inhibitor YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole). Furthermore, we found that the conditioned medium from estrogen treated thyroid cancer cells lead to enhanced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs) which is abrogated by HIF-1 inhibitor. These findings, in addition to our previous and other scientific literature data, lead us to conclude that estrogen and hypoxia are interlinked in thyroid cancer and can equally modulate epithelial-endothelial cell interactions by mediating key cellular, metabolic and molecular processes of thyroid cancer progression. We believe that the hormonal component and cellular adaptation to oxygen tension of cancer cells are functionally equivalent with a cellular transition that can be exploited clinically for a combinational approach for thyroid cancer treatment involving antiestrogens as well as anti-hypoxic agents.

  1. Volumetric modulated arc radiotherapy sparing the thyroid gland for early-stage glottic cancer: A dosimetrical analysis.

    Science.gov (United States)

    Kim, Eun Seok; Yeo, Seung-Gu

    2014-06-01

    Previous studies on advanced radiotherapy (RT) techniques for early stage glottic cancer have focused on sparing the carotid artery. However, the aim of the present study was to evaluate the dosimetric advantages of volumetric modulated arc therapy (VMAT) in terms of sparing the thyroid gland in early-stage glottic cancer patients. In total, 15 cT1N0M0 glottic cancer patients treated with definitive RT using VMAT were selected, and for dosimetric comparison, a conventional RT plan comprising opposed-lateral wedged fields was generated for each patient. The carotid artery, thyroid gland and spinal cord were considered organs at risk. The prescription dose was 63 Gy at 2.25 Gy per fraction. For the thyroid gland and carotid artery, all compared parameters were significantly lower with VMAT compared with conventional RT. For the thyroid gland, the median reduction rates of the mean dose (Dmean), the volume receiving ≥30% of the prescription dose (V30) and the V50 were 32.6, 40.9 and 46.0%, respectively. The Dmean was 14.7±2.6 Gy when using VMAT compared with 22.2±3.9 Gy when using conventional RT. The differences between the techniques in terms of planning target volume coverage and dose homogeneity were not significant. When considering a recent normal tissue complication probability model, which indicated the mean thyroid gland dose as the most significant predictor of radiation-induced hypothyroidism, the dosimetric advantage shown in this study may be valuable in reducing hypothyroidism following RT for early stage glottic cancer patients.

  2. Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4.

    Science.gov (United States)

    Casillan, Alfred J; Gonzalez, Norberto C; Johnson, Jennifer S; Steiner, Dawn R S; Wood, John G

    2003-06-01

    Systemic hypoxia produces a rapid microvascular inflammatory response characterized by increased reactive oxygen species (ROS) levels, leukocyte-endothelial adherence and emigration, and increased vascular permeability. The lipid inflammatory mediator leukotriene B(4) (LTB(4)) is involved in the early hypoxia-induced responses (ROS generation and leukocyte adherence). Whether other lipid inflammatory mediators participate in this phenomenon is not known. The objective of these experiments was to study the role of platelet-activating factor (PAF) in the microvascular inflammatory response to hypoxia and its potential interactions with LTB(4) in this response. Intravital microscopy was used to examine mesenteric venules of anesthetized rats. We found that WEB-2086, a PAF receptor antagonist, completely prevented the increase in ROS levels and leukocyte adherence during a brief reduction in inspired Po(2) to anesthetized rats; administration of either WEB-2086 or the LTB(4) antagonist LTB(4)-DMA attenuated leukocyte emigration and the increase in vascular permeability to the same extent during prolonged systemic hypoxia in conscious rats. Furthermore, no additive effect was observed in either response when both antagonists were administered simultaneously. This study demonstrates a role for PAF in the rapid microvascular inflammatory response to hypoxia, as well as contributions of PAF and LTB(4) to the slowly developing responses observed during sustained hypoxia. The incomplete blockade of the hypoxia-induced increases in vascular permeability and leukocyte emigration by combined administration of both antagonists indicates that factors in addition to LTB(4) and PAF participate in these phenomena.

  3. The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS

    Directory of Open Access Journals (Sweden)

    Gatambwa Mukandala

    2016-02-01

    Full Text Available Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event.

  4. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

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

    1998-01-01

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

  5. Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.

    Science.gov (United States)

    Torres, Marta; Palomer, Xavier; Montserrat, Josep M; Vázquez-Carrera, Manel; Farré, Ramon

    2014-10-01

    Patient data report marked gender and pre-vs-postmenopausal differences in obstructive sleep apnea (OSA). However, no experimental data are available on how sexual hormones modulate OSA consequences. Here we report novel results on estrogen-modulated heart and brain inflammation in female mice subjected to intermittent hypoxia, a major injurious challenge in OSA. C57BL/6J (14-week old) intact and ovariectomized mice (n=6 each) were subjected to intermittent hypoxia (20 s at 5% and 40s at 21%, 60 cycles/h; 6 h/day). Identical intact and ovariectomized groups breathing room air were controls. After 30 days, the gene expressions of interleukins 6 and 8 (IL-6, IL-8) in the brain and heart tissues were measured. Whereas, compared with normoxia, intermittent hypoxia considerably increased IL-6 and IL-8 gene expressions in intact females, no change was found in ovariectomized mice when comparing normoxia and intermittent hypoxia. These data suggest that estrogens modulate the inflammatory effects of intermittent hypoxia and point to further studies on the role played by sex hormones in OSA.

  6. Superficial Collagen Fibril Modulus and Pericellular Fixed Charge Density Modulate Chondrocyte Volumetric Behaviour in Early Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Petri Tanska

    2013-01-01

    Full Text Available The aim of this study was to investigate if the experimentally detected altered chondrocyte volumetric behavior in early osteoarthritis can be explained by changes in the extracellular and pericellular matrix properties of cartilage. Based on our own experimental tests and the literature, the structural and mechanical parameters for normal and osteoarthritic cartilage were implemented into a multiscale fibril-reinforced poroelastic swelling model. Model simulations were compared with experimentally observed cell volume changes in mechanically loaded cartilage, obtained from anterior cruciate ligament transected rabbit knees. We found that the cell volume increased by 7% in the osteoarthritic cartilage model following mechanical loading of the tissue. In contrast, the cell volume decreased by 4% in normal cartilage model. These findings were consistent with the experimental results. Increased local transversal tissue strain due to the reduced collagen fibril stiffness accompanied with the reduced fixed charge density of the pericellular matrix could increase the cell volume up to 12%. These findings suggest that the increase in the cell volume in mechanically loaded osteoarthritic cartilage is primarily explained by the reduction in the pericellular fixed charge density, while the superficial collagen fibril stiffness is suggested to contribute secondarily to the cell volume behavior.

  7. The consumption of n-3 polyunsaturated fatty acids differentially modulates gene expression of peroxisome proliferator-activated receptor alpha and gamma and hypoxia-inducible factor 1 alpha in subcutaneous adipose tissue of obese adolescents.

    Science.gov (United States)

    Mejía-Barradas, César M; Del-Río-Navarro, Blanca E; Domínguez-López, Aarón; Campos-Rodríguez, Rafael; Martínez-Godínez, María de-Los-Á; Rojas-Hernández, Saúl; Lara-Padilla, Eleazar; Abarca-Rojano, Edgar; Miliar-García, Ángel

    2014-02-01

    The aim of this study was to evaluate the effect of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on metabolic state and gene expression in subcutaneous adipose tissues of obese adolescents. Obese adolescents (n = 26, 10 girls and 16 boys) aged 12.4 ± 2.1 years were assigned to a 12-week regimen of n-3 PUFA intake. Five times per day, subjects received a food supplement consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (3 g per day, 944 mg EPA, and 2,088 mg DHA). Blood parameters were measured, and subcutaneous adipose tissue biopsies were analyzed to determine gene expression at baseline and after 12 weeks. Student's t test and the Wilcoxon signed-rank test were used to estimate differences in arithmetic means of pre- and post-dietary supplementation for various anthropometric, biochemical, clinical, and gene expression parameters. After 12 weeks, n-3 PUFA consumption was associated with decreased body mass index (29.7 ± 4.6 vs. 27.8 ± 4.4 kg/m(2); P Fatty acid supplementation/n3 PUFA supplementation was associated with a downregulated expression of the genes encoding PPARγ and PGC-1α (P consumption and dietary restriction improved the anthropometric parameters and decreased the triglycerides levels of the adolescents, suggesting a reduction in hypoxia in subcutaneous adipose tissue.

  8. Exogenous nitric oxide (NO) generated by NO-plasma treatment modulates osteoprogenitor cells early differentiation

    Science.gov (United States)

    Elsaadany, Mostafa; Subramanian, Gayathri; Ayan, Halim; Yildirim-Ayan, Eda

    2015-09-01

    In this study, we investigated whether nitric oxide (NO) generated using a non-thermal plasma system can mediate osteoblastic differentiation of osteoprogenitor cells without creating toxicity. Our objective was to create an NO delivery mechanism using NO-dielectric barrier discharge (DBD) plasma that can generate and transport NO with controlled concentration to the area of interest to regulate osteoprogenitor cell activity. We built a non-thermal atmospheric pressure DBD plasma nozzle system based on our previously published design and similar designs in the literature. The electrical and spectral analyses demonstrated that N2 dissociated into NO under typical DBD voltage-current characteristics. We treated osteoprogenitor cells (MC3T3-E1) using NO-plasma treatment system. Our results demonstrated that we could control NO concentration within cell culture media and could introduce NO into the intracellular space using NO-plasma treatment with various treatment times. We confirmed that NO-plasma treatment maintained cell viability and did not create any toxicity even with prolonged treatment durations. Finally, we demonstrated that NO-plasma treatment induced early osteogenic differentiation in the absence of pro-osteogenic growth factors/proteins. These findings suggest that through the NO-plasma treatment system we are able to generate and transport tissue-specific amounts of NO to an area of interest to mediate osteoprogenitor cell activity without subsequent toxicity. This opens up the possibility to develop DBD plasma-assisted tissue-specific NO delivery strategies for therapeutic intervention in the prevention and treatment of bone diseases.

  9. Supramolecular structure of dietary fat in early life modulates expression of markers for mitochondrial content and capacity in adipose tissue of adult mice

    NARCIS (Netherlands)

    Kodde, Andrea; van der Beek, Eline M.; Phielix, Esther; Engels, Eefje; Schipper, Lidewij; Oosting, Annemarie

    2017-01-01

    Background: Previous studies have shown that early life nutrition can modulate the development of white adipose tissue and thereby affect the risk on obesity and metabolic disease later in life. For instance, postnatal feeding with a concept infant milk formula with large, phospholipid coated lipid

  10. MRI-guided single fraction ablative radiotherapy for early-stage breast cancer : a brachytherapy versus volumetric modulated arc therapy dosimetry study

    NARCIS (Netherlands)

    Charaghvandi, Ramona K; den Hartogh, Mariska D; van Ommen, Anne-Mar L N; de Vries, Wilfred J H; Scholten, Vincent; Moerland, Rien; Philippens, Mariëlle E P; Schokker, Rogier I; van Vulpen, Marco; van Asselen, B; van den Bongard, Desirée H J G

    2015-01-01

    BACKGROUND AND PURPOSE: A radiosurgical treatment approach for early-stage breast cancer has the potential to minimize the patient's treatment burden. The dosimetric feasibility for single fraction ablative radiotherapy was evaluated by comparing volumetric modulated arc therapy (VMAT) with an inter

  11. Interannual modulation of East African early short rains by the winter Arctic Oscillation

    Science.gov (United States)

    Gong, Dao-Yi; Guo, Dong; Mao, Rui; Yang, Jing; Gao, Yongqi; Kim, Seong-Joong

    2016-08-01

    In the present study, we analyzed the interannual linkage between the boreal winter Arctic Oscillation (AO) and East African early short rains. When the Indian Ocean Dipole and El Niño-Southern Oscillation variance are excluded by linear regression, the boreal winter AO index is significantly correlated with the October East African precipitation over the domain of 5°N-5°S and 35°-45°E for the period 1979-2014, r =+ 0.46. The upper ocean heat content likely acts as a medium that links the AO and East African precipitation. Significant subsurface warming and positive upper ocean heat content anomalies occur over the western Indian Ocean during the autumn following positive AO winters, which enriches the atmospheric moisture, intensifies convection, and enhances precipitation. Oceanic dynamics play a key role in causing this subsurface warming. Winter AO-related atmospheric circulation creates anomalous wind stress, which forces a downwelling oceanic Rossby wave between 60°-75°E and 5°-10°S, where the thermocline significantly deepens. This Rossby wave propagates westward and accompanies significant subsurface warming along the thermocline. The Rossby wave arrives at the western Indian Ocean in the late summer, significantly warming the region to the west of 55°E at a depth of 60-100 m. This warming remains significant through October. Correspondingly, the upper ocean heat content significantly increases by approximately 2-3 × 108 J m-2 in the region west of 60°E between 5° and 10°S. The role of these oceanic dynamics in linking the winter AO, and anomalous subsurface warming was tested by numerical experiments with an oceanic general circulation model. The experiments were performed with the forcing of AO-related wind stress anomalies over the Indian Ocean in the winter. The oceanic Rossby wave generated in the central Indian Ocean during boreal winter, the consequent subsurface warming, and the anomalous upper ocean heat content in October over the

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

    Directory of Open Access Journals (Sweden)

    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

  13. Electrical signaling, stomatal conductance, ABA and ethylene content in avocado trees in response to root hypoxia.

    Science.gov (United States)

    Gil, Pilar M; Gurovich, Luis; Schaffer, Bruce; García, Nicolás; Iturriaga, Rodrigo

    2009-02-01

    Avocado (Persea americana Mill.) trees are among the most sensitive of fruit tree species to root hypoxia as a result of flooded or poorly drained soil. Similar to drought stress, an early physiological response to root hypoxia in avocado is a reduction of stomatal conductance. It has been previously determined in avocado trees that an extracellular electrical signal between the base of stem and leaves is produced and related to reductions in stomatal conductance in response to drought stress. The current study was designed to determine if changes in the extracellular electrical potential between the base of the stem and leaves in avocado trees could also be detected in response to short-term (min) or long-term (days) root hypoxia, and if these signals could be related to stomatal conductance (gs), root and leaf ABA and ACC concentrations, ethylene emission from leaves and leaf abscission. In contrast to previous observations for drought-stressed trees, short-term or long-term root hypoxia did not stimulate an electrical potential difference between the base of the stem and leaves. Short-term hypoxia did not result in a significant decrease in gs compared with plants in the control treatment, and no differences in ABA concentration were found between plants subjected to hypoxia and control plants. Long-term hypoxia in the root zone resulted in a significant decrease in gs, increased leaf ethylene and increased leaf abscission. The results indicate that for avocado trees exposed to root hypoxia, electrical signals do not appear to be the primary root-to-shoot communication mechanism involved in signaling for stomatal closure as a result of hypoxia in the root zone.

  14. Electrical signaling, stomatal conductance, ABA and Ethylene content in avocado trees in response to root hypoxia

    Science.gov (United States)

    Gurovich, Luis; Schaffer, Bruce; García, Nicolás; Iturriaga, Rodrigo

    2009-01-01

    Avocado (Persea americana Mill.) trees are among the most sensitive of fruit tree species to root hypoxia as a result of flooded or poorly drained soil. Similar to drought stress, an early physiological response to root hypoxia in avocado is a reduction of stomatal conductance. It has been previously determined in avocado trees that an extracellular electrical signal between the base of stem and leaves is produced and related to reductions in stomatal conductance in response to drought stress. The current study was designed to determine if changes in the extracellular electrical potential between the base of the stem and leaves in avocado trees could also be detected in response to short-term (min) or long-term (days) root hypoxia, and if these signals could be related to stomatal conductance (gs), root and leaf ABA and ACC concentrations, ethylene emission from leaves and leaf abscission. In contrast to previous observations for drought-stressed trees, short-term or long-term root hypoxia did not stimulate an electrical potential difference between the base of the stem and leaves. Short-term hypoxia did not result in a significant decrease in gs compared with plants in the control treatment, and no differences in ABA concentration were found between plants subjected to hypoxia and control plants. Long-term hypoxia in the root zone resulted in a significant decrease in gs, increased leaf ethylene and increased leaf abscission. The results indicate that for avocado trees exposed to root hypoxia, electrical signals do not appear to be the primary root-to-shoot communication mechanism involved in signaling for stomatal closure as a result of hypoxia in the root zone. PMID:19649181

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

    Directory of Open Access Journals (Sweden)

    S. A. Perepelitsa

    2012-01-01

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

  16. The early nutritional environment of mice determines the capacity for adipose tissue expansion by modulating genes of caveolae structure.

    Directory of Open Access Journals (Sweden)

    Leslie P Kozak

    Full Text Available While the phenomenon linking the early nutritional environment to disease susceptibility exists in many mammalian species, the underlying mechanisms are unknown. We hypothesized that nutritional programming is a variable quantitative state of gene expression, fixed by the state of energy balance in the neonate, that waxes and wanes in the adult animal in response to changes in energy balance. We tested this hypothesis with an experiment, based upon global gene expression, to identify networks of genes in which expression patterns in inguinal fat of mice have been altered by the nutritional environment during early post-natal development. The effects of over- and under-nutrition on adiposity and gene expression phenotypes were assessed at 5, 10, 21 days of age and in adult C57Bl/6J mice fed chow followed by high fat diet for 8 weeks. Under-nutrition severely suppressed plasma insulin and leptin during lactation and diet-induced obesity in adult mice, whereas over-nourished mice were phenotypically indistinguishable from those on a control diet. Food intake was not affected by under- or over-nutrition. Microarray gene expression data revealed a major class of genes encoding proteins of the caveolae and cytoskeleton, including Cav1, Cav2, Ptrf (Cavin1, Ldlr, Vldlr and Mest, that were highly associated with adipose tissue expansion in 10 day-old mice during the dynamic phase of inguinal fat development and in adult animals exposed to an obesogenic environment. In conclusion gene expression profiles, fat mass and adipocyte size in 10 day old mice predicted similar phenotypes in adult mice with variable diet-induced obesity. These results are supported by phenotypes of KO mice and suggest that when an animal enters a state of positive energy balance adipose tissue expansion is initiated by coordinate changes in mRNA levels for proteins required for modulating the structure of the caveolae to maximize the capacity of the adipocyte for lipid storage.

  17. Quantitative analysis of ChIP-seq data uncovers dynamic and sustained H3K4me3 and H3K27me3 modulation in cancer cells under hypoxia.

    Science.gov (United States)

    Adriaens, Michiel E; Prickaerts, Peggy; Chan-Seng-Yue, Michelle; van den Beucken, Twan; Dahlmans, Vivian E H; Eijssen, Lars M; Beck, Timothy; Wouters, Bradly G; Voncken, Jan Willem; Evelo, Chris T A

    2016-01-01

    A comprehensive assessment of the epigenetic dynamics in cancer cells is the key to understanding the molecular mechanisms underlying cancer and to improving cancer diagnostics, prognostics and treatment. By combining genome-wide ChIP-seq epigenomics and microarray transcriptomics, we studied the effects of oxygen deprivation and subsequent reoxygenation on histone 3 trimethylation of lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in a breast cancer cell line, serving as a model for abnormal oxygenation in solid tumors. A priori, epigenetic markings and gene expression levels not only are expected to vary greatly between hypoxic and normoxic conditions, but also display a large degree of heterogeneity across the cell population. Where traditionally ChIP-seq data are often treated as dichotomous data, the model and experiment here necessitate a quantitative, data-driven analysis of both datasets. We first identified genomic regions with sustained epigenetic markings, which provided a sample-specific reference enabling quantitative ChIP-seq data analysis. Sustained H3K27me3 marking was located around centromeres and intergenic regions, while sustained H3K4me3 marking is associated with genes involved in RNA binding, translation and protein transport and localization. Dynamic marking with both H3K4me3 and H3K27me3 (hypoxia-induced bivalency) was found in CpG-rich regions at loci encoding factors that control developmental processes, congruent with observations in embryonic stem cells. In silico-identified epigenetically sustained and dynamic genomic regions were confirmed through ChIP-PCR in vitro, and obtained results are corroborated by published data and current insights regarding epigenetic regulation.

  18. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease.

    Science.gov (United States)

    Lefere, Sander; Van Steenkiste, Christophe; Verhelst, Xavier; Van Vlierberghe, Hans; Devisscher, Lindsey; Geerts, Anja

    2016-09-01

    The pandemic rise in obesity has resulted in an increased incidence of metabolic complications. Non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome and has become the most common chronic liver disease in large parts of the world. The adipose tissue expansion and hepatic fat accumulation characteristics of these disorders compromise local oxygen homeostasis. The resultant tissue hypoxia induces adaptive responses to restore oxygenation and tissue metabolism and cell survival. Hypoxia-inducible factors (HIFs) function as master regulators of this hypoxia adaptive response, and are in turn hydroxylated by prolyl hydroxylases (PHDs). PHDs are the main cellular oxygen sensors and regulate HIF proteasomal degradation in an oxygen-dependent manner. HIFs and PHDs are implicated in numerous physiological and pathological conditions. Extensive research using genetic models has revealed that hypoxia signaling is also a key mechanism in adipose tissue dysfunction, leading to adipose tissue fibrosis, inflammation and insulin resistance. Moreover, hypoxia affects liver lipid metabolism and deranges hepatic lipid accumulation. This review summarizes the molecular mechanisms through which the hypoxia adaptive response affects adipocyte and hepatic metabolism, and the therapeutic possibilities of modulating HIFs and PHDs in obesity and fatty liver disease.

  19. [Protective effect of salidroside against high altitude hypoxia-induced brain injury in rats].

    Science.gov (United States)

    Dong, Xiaoru; Zhang, Xiangnan; Li, Dan; Li, Bin; Wang, Jiye; Meng, Shanshan; Luo, Wenjing; Zhang, Wenbin

    2015-10-01

    To observe the protective effect of salidroside against brain injury in rats exposed to hypobaric hypoxia, and investigate the molecular mechanism of salidroside in the prevention of hypobaric hypoxia-induced brain injury. Rats were placed in experiment module simulating 6000 m altitude to establish acute hypobaric hypoxia-induced brain injury models. Their respiratory frequency was observed and recorded. Cell apoptosis in the hippocampal dentate gyrus (DG) was detected by TUNEL assay; the expressions of Ras homolog family member A (RhoA), phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected by Western blotting. After acute exposure to 6000 m altitude, the respiratory frequency of the rats increased remarkably. The simulation of hypobaric hypoxia induced cell apoptosis in hippocampal DG region, and salidroside intervention inhibited the process of cell apoptosis. The expressions of RhoA, p-ERK, p-JNK decreased after hypobaric hypoxia exposure. Salidroside intervention reversed RhoA expression and raised the levels of p-ERK and p-JNK. Acute exposure to hypobaric hypoxia can induce cell apoptosis in rat hippocampal DG, and salidroside can protect the cells from the exposure-induced apoptosis.

  20. Cyclin G2 Promotes Hypoxia- Driven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics

    Directory of Open Access Journals (Sweden)

    Atsushi Fujimura

    2013-11-01

    Full Text Available Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.

  1. Long-term results of forward intensity-modulated radiation therapy for patients with early-stage breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Boram; Suh, Hyun Suk; Lee, Ji Hae; Lee, Kyung Ja; Lee, Rena; Moon, Byung In [Ewha Womans University College of Medicine, Seoul (Korea, Republic of)

    2013-12-15

    To observe long-term clinical outcomes for patients with early-stage breast cancer treated with forward intensity-modulated radiation therapy (IMRT), including local control and clinical toxicities. We retrospectively analyzed a total of 214 patients with stage I-II breast cancer who were treated with breast conserving surgery followed by adjuvant breast radiation therapy between 2001 and 2008. All patients were treated using forward IMRT. The whole breast was irradiated to a dose of 50 to 50.4 Gy followed by an 8 to 12 Gy electron boost to the surgical bed. The median age was 46 years (range, 21 to 82 years) and the medial follow-up time was 7.3 years (range, 2.4 to 11.7 years). Stage T1 was 139 (65%) and T2 was 75 (35%), respectively. Ipsilateral breast recurrence was observed in 3 patients. The 5- and 10-year local control rates were 99.1% and 97.8%, respectively. The cosmetic outcome was evaluated according to the Harvard scale and 89.4% of patients were scored as excellent or good. The whole breast radiation therapy as an adjuvant treatment using a forward IMRT technique showed excellent long-term local control as well as favorable outcomes of toxicity and cosmesis.

  2. 缺氧后内皮细胞早期生长反应因子-1活化的信号机制%The Signaling Mechanism Involved in Hypoxia-induced Upregulation of Early Growth Response-1 in Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    黄春; 杨明; 施晓芸; 陈晓春

    2012-01-01

    目的 观察缺氧对内皮细胞早期生长反应因子(Egr-1)表达的影响及晚期糖基化终末产物(AGEs)及其受体(RAGE)对上述效应的可能调控机制.方法 以培养小鼠主动脉内皮细胞(MAECs)为模型,根据缺氧时间和缺氧前预处理方式,分为不同缺氧时间组[缺氧0(对照组),5,10,15,30,60,120 min组]、anti-AGE预处理组、可溶性RAGE(sRAGE)预处理组和蛋白激酶C(PKC)β抑制剂组,实时定量PCR法检测缺氧后Egr-1 mRNA含量、ELISA法检测细胞裂解液中AGEs含量、蛋白印迹法检测细胞膜蛋白中PKC各异构体的活化.结果 缺氧15 min组Egr-1 mRNA表达上调,为对照组的(14.13±0.77)倍(P=0.000 0);缺氧10~60 min内皮细胞裂解液中AGEs堆积;缺氧15 min组MAECs膜蛋白中PKCβⅡ含量为(30.57±1.86),显著高于对照组的含量(9.22±1.05)(P=0.002);anti-AGE、sRAGE和PKCβ抑制剂预处理减少缺氧诱导的Egr-1 mRNA表达上调(P=0.000 0);anti-AGE和sRAGE预处理显著减少缺氧对PKCβⅡ的活化(P=0.000 0).结论 急性缺氧诱导内皮细胞AGEs堆积、PKCβⅡ活化和Egr-1mRNA高表达,AGEs-RAGE和PKCβII信号参与急性缺氧后Egr-1诱导表达的调控.%Objective To observe the impact of hypoxia on the expression of early growth response-1 (Egr-1) in mouse aortic endothelial cells(MAECs) , and to study the underlying signaling mechanism involving advanced glycation end-products (AGEs) and its receptor (receptor for AGEs, RAGE). Methods MAECs were subjected to hypoxia treatment with a (6.0+0.5)% oxygen concentration for various periods (0, 5, 10, 15, 30, 60 or 120 min) , or -were first pre-incubated -with anti-AGEs or soluble RAGE (sRAGE) for 2 h, or LY379196 for 45 min respectively, and then subsequently exposed to hypoxia for 15 min. Egr-1 mRNA levels -were detected by real time PCR (RT-PCR), AGEs in cell lysate -were monitored by ELISA, and PKC isoformates in membrane fraction were examined by western blot. MAECs cultured -with normoxia -were

  3. Long-Term Outcomes of Early-Stage Nasopharyngeal Carcinoma Patients Treated With Intensity-Modulated Radiotherapy Alone

    Energy Technology Data Exchange (ETDEWEB)

    Su Shengfa [State Key Laboratory of Oncology in Southern China, Guangzhou (China); Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Department of Oncology, GuiYang Medical College Hospital, Guiyang, Guizhou (China); Han Fei; Zhao Chong; Chen Chunyan; Xiao Weiwei; Li Jiaxin [State Key Laboratory of Oncology in Southern China, Guangzhou (China); Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou (China); Lu Taixiang, E-mail: ssf2010@sina.cn [State Key Laboratory of Oncology in Southern China, Guangzhou (China); Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou (China)

    2012-01-01

    Purpose: Reports of intensity-modulated radiotherapy (IMRT) for early-stage nasopharyngeal carcinoma (NPC) have been limited. The present study evaluated the long-term survival outcomes and toxicity of early-stage NPC patients treated with IMRT alone. Methods and Materials: Between February 2001 and January 2008, 198 early-stage (T1-T2bN0-N1M0) NPC patients had undergone IMRT alone. The data from these patients were retrospectively analyzed. The patients were treated to 68 Gy at 2.27 Gy/fraction prescribed to the planning target volume of the primary nasopharygeal gross tumor volume. The Radiation Therapy Oncology Group scoring system was used to assess the toxicity. Results: At a median follow-up of 50.9 months (range, 12-104), the 5-year estimated disease-specific survival, local recurrence-free survival, and distant metastasis-free survival rate was 97.3%, 97.7%, and 97.8%, respectively. The 5-year local recurrence-free survival rate was 100% for those with Stage T1 and T2a and 94.2% for those with Stage T2b lesions (p = 0.252). The 5-year distant metastasis-free survival rate for Stage T1N0, T2N0, T1N1, and T2N1 patients was 100%, 98.8%, 100%, and 93.8%, respectively (p = .073). All local recurrence occurred in patients with T2b lesions. Five patients developed distant metastasis. Of these 5 patients, 4 had had Stage T2bN1 disease and 1 had had Stage T2bN0 disease with retropharyngeal lymph node involvement. The most common acute toxicities were mainly Grade 1 or 2. At 24 months after IMRT, no Grade 3 or 4 xerostomia had developed, and 62 (96.9%) of 64 evaluated patients were free of trismus; only 2 patients (3.1%) had Grade 1 trismus. Radiation encephalopathy and cranial nerve injury were not observed. Conclusions: IMRT alone for Stage T1N0, T2N0, T1N1, and T2N1 yielded satisfactory survival outcomes with acceptable toxicity, and no differences were found in survival outcomes among these four subgroups. Patients with Stage T2b lesions might have relatively

  4. Emerging evidence of the physiological role of hypoxia in mammary development and lactation

    Institute of Scientific and Technical Information of China (English)

    Yong Shao; Feng-Qi Zhao

    2014-01-01

    Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting ofαandβsubunits. HIF-1βis constantly expressed, whereas HIF-1αis degraded under normal oxygen conditions. Hypoxia stabilizes HIF-1αand the HIF complex, and HIF then translocates into the nucleus to initiate the expression of target genes. Hypoxia has been extensively studied for its role in promoting tumor progression, and emerging evidence also indicates that hypoxia may play important roles in physiological processes, including mammary development and lactation. The mammary gland exhibits an increasing metabolic rate from pregnancy to lactation to support mammary growth, lactogenesis, and lactation. This process requires increasing amounts of oxygen consumption and results in localized chronic hypoxia as confirmed by the binding of the hypoxia marker pimonidazole HCl in mouse mammary gland. We hypothesized that this hypoxic condition promotes mammary development and lactation, a hypothesis that is supported by the following several lines of evidence:i) Mice with an HIF-1αdeletion selective for the mammary gland have impaired mammary differentiation and lipid secretion, resulting in lactation failure and striking changes in milk compositions;ii) We recently observed that hypoxia significantly induces HIF-1α-dependent glucose uptake and GLUT1 expression in mammary epithelial cells, which may be responsible for the dramatic increases in glucose uptake and GLUT1 expression in the mammary gland during the transition period from late pregnancy to early lactation;and ii ) Hypoxia and HIF-1αincrease the

  5. A Zebrafish Model to Study and Therapeutically Manipulate Hypoxia Signaling in Tumorigenesis

    NARCIS (Netherlands)

    Santhakumar, Kirankumar; Judson, Emma C.; Elks, Philip M.; McKee, Sarah; Elworthy, Stone; van Rooijen, Ellen; Walmsley, Sarah S.; Renshaw, Stephen A.; Cross, Simon S.; van Eeden, Fredericus J. M.

    2012-01-01

    Hypoxic signaling is a central modulator of cellular physiology in cancer. Core members of oxygen-sensing pathway including the von Hippel-Lindau tumor suppressor protein (pVHL) and the hypoxia inducible factor (HIF) transcription factors have been intensively studied, but improved organismal models

  6. Hypoxia Impairs Vasodilation in the Lung

    OpenAIRE

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

    1981-01-01

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

  7. The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching.

    Science.gov (United States)

    Umbrello, Michele; Dyson, Alex; Feelisch, Martin; Singer, Mervyn

    2013-11-10

    A mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow--hypoxic vasodilation--occur in an attempt to restore oxygen supply. Nitric oxide (NO) is a major signaling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). This review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of NO, and mechanisms underlying the involvement of NO in hypoxic vasodilation. Recent insights into NO metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite (NO₂⁻) reductases, and release of NO from storage pools. The processes through which NO levels are elevated during hypoxia are presented, namely, (i) increased synthesis from NO synthases, increased reduction of NO₂⁻ to NO by heme- or pterin-based enzymes and increased release from NO stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Several reviews covered modulation of energetic metabolism by NO, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression. We identify a key position for NO in the body's adaptation to an acute energy supply-demand mismatch.

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

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

  9. Brain dysfunction in mild to moderate hypoxia.

    Science.gov (United States)

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

    1981-06-01

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

  10. Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

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    Mohammad Badran

    2016-01-01

    Full Text Available Objective. Obstructive sleep apnea (OSA, characterized by chronic intermittent hypoxia (CIH, is often present in diabetic (DB patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb/J (db/db mice (10 weeks old and their heterozygote littermates were subjected to CIH or intermittent air (IA for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic, IH (intermittent hypoxia nondiabetic, IADB (intermittent air diabetic, and IHDB (intermittent hypoxia diabetic groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6, and asymmetric dimethylarginine (ADMA were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

  11. Quantification of tumour hypoxia. Functional histology and autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Bussink, J. [Radboud Univ. Nijmegen Medical Centre (Netherlands). Dept. of Radiation Oncology

    2010-07-01

    Tumor cell hypoxia is considered one of the important causes for radiation resistance. The introduction of IMRT (intensity modulated radiotherapy) allows specific boosting of tumor subvolumes that may harbour these radioresistant tumour cells. PET imaging of these subvolumes can be incorporated into treatment planning. However, at this moment microenvironmental changes visualized and quantified by means of PET-imaging need to be validated by high-resolution microscopic techniques. This will allow interpretation of imaging techniques with intermediate resolution (such as PET/CT) in relation to complex cellular signaling in response to anti-cancer treatments. (orig.)

  12. Involved-Site Image-Guided Intensity Modulated Versus 3D Conformal Radiation Therapy in Early Stage Supradiaphragmatic Hodgkin Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Filippi, Andrea Riccardo, E-mail: andreariccardo.filippi@unito.it [Department of Oncology, University of Torino, Torino (Italy); Ciammella, Patrizia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Piva, Cristina; Ragona, Riccardo [Department of Oncology, University of Torino, Torino (Italy); Botto, Barbara [Hematology, Città della Salute e della Scienza, Torino (Italy); Gavarotti, Paolo [Hematology, University of Torino and Città della Salute e della Scienza, Torino (Italy); Merli, Francesco [Hematology Unit, ASMN Hospital IRCCS, Reggio Emilia (Italy); Vitolo, Umberto [Hematology, Città della Salute e della Scienza, Torino (Italy); Iotti, Cinzia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Ricardi, Umberto [Department of Oncology, University of Torino, Torino (Italy)

    2014-06-01

    Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows for margin reduction and highly conformal dose distribution, with consistent advantages in sparing of normal tissues. The purpose of this retrospective study was to compare involved-site IG-IMRT with involved-site 3D conformal RT (3D-CRT) in the treatment of early stage Hodgkin lymphoma (HL) involving the mediastinum, with efficacy and toxicity as primary clinical endpoints. Methods and Materials: We analyzed 90 stage IIA HL patients treated with either involved-site 3D-CRT or IG-IMRT between 2005 and 2012 in 2 different institutions. Inclusion criteria were favorable or unfavorable disease (according to European Organization for Research and Treatment of Cancer criteria), complete response after 3 to 4 cycles of an adriamycin- bleomycin-vinblastine-dacarbazine (ABVD) regimen plus 30 Gy as total radiation dose. Exclusion criteria were chemotherapy other than ABVD, partial response after ABVD, total radiation dose other than 30 Gy. Clinical endpoints were relapse-free survival (RFS) and acute toxicity. Results: Forty-nine patients were treated with 3D-CRT (54.4%) and 41 with IG-IMRT (45.6%). Median follow-up time was 54.2 months for 3D-CRT and 24.1 months for IG-IMRT. No differences in RFS were observed between the 2 groups, with 1 relapse each. Three-year RFS was 98.7% for 3D-CRT and 100% for IG-IMRT. Grade 2 toxicity events, mainly mucositis, were recorded in 32.7% of 3D-CRT patients (16 of 49) and in 9.8% of IG-IMRT patients (4 of 41). IG-IMRT was significantly associated with a lower incidence of grade 2 acute toxicity (P=.043). Conclusions: RFS rates at 3 years were extremely high in both groups, albeit the median follow-up time is different. Acute tolerance profiles were better for IG-IMRT than for 3D-CRT. Our preliminary results support the clinical safety and efficacy of advanced RT planning and delivery techniques in patients affected with early stage HL, achieving complete

  13. 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.

  14. 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.

  15. Temperature modulates the response of the thermophilous sea urchin Arbacia lixula early life stages to CO2-driven acidification.

    Science.gov (United States)

    Gianguzza, Paola; Visconti, Giulia; Gianguzza, Fabrizio; Vizzini, Salvatrice; Sarà, Gianluca; Dupont, Sam

    2014-02-01

    The increasing abundances of the thermophilous black sea urchin Arbacia lixula in the Mediterranean Sea are attributed to the Western Mediterranean warming. However, few data are available on the potential impact of this warming on A. lixula in combination with other global stressors such as ocean acidification. The aim of this study is to investigate the interactive effects of increased temperature and of decreased pH on fertilization and early development of A. lixula. This was tested using a fully crossed design with four temperatures (20, 24, 26 and 27 °C) and two pH levels (pHNBS 8.2 and 7.9). Temperature and pH had no significant effect on fertilization and larval survival (2d) for temperature <27 °C. At 27 °C, the fertilization success was very low (<1%) and all larvae died within 2d. Both temperature and pH had effects on the developmental dynamics. Temperature appeared to modulate the impact of decreasing pH on the % of larvae reaching the pluteus stage leading to a positive effect (faster growth compared to pH 8.2) of low pH at 20 °C, a neutral effect at 24 °C and a negative effect (slower growth) at 26 °C. These results highlight the importance of considering a range of temperatures covering today and the future environmental variability in any experiment aiming at studying the impact of ocean acidification.

  16. Intensity modulated radiotherapy in early stage Hodgkin lymphoma patients: Is it better than three dimensional conformal radiotherapy?

    Directory of Open Access Journals (Sweden)

    De Sanctis Vitaliana

    2012-08-01

    Full Text Available Abstract Background Cure rate of early Hodgkin Lymphoma are high and avoidance of late toxicities is of paramount importance. This comparative study aims to assess the normal tissue sparing capability of intensity-modulated radiation therapy (IMRT versus standard three-dimensional conformal radiotherapy (3D-CRT in terms of dose-volume parameters and normal tissue complication probability (NTCP for different organs at risk in supradiaphragmatic Hodgkin Lymphoma (HL patients. Methods Ten HL patients were actually treated with 3D-CRT and all treatments were then re-planned with IMRT. Dose-volume parameters for thyroid, oesophagus, heart, coronary arteries, lung, spinal cord and breast were evaluated. Dose-volume histograms generated by TPS were analyzed to predict the NTCP for the considered organs at risk, according to different endpoints. Results Regarding dose-volume parameters no statistically significant differences were recorded for heart and origin of coronary arteries. We recorded statistically significant lower V30 with IMRT for oesophagus (6.42 vs 0.33, p = 0.02 and lungs (4.7 vs 0.1 p = 0.014 for the left lung and 2.59 vs 0.1 p = 0.017 for the right lung and lower V20 for spinal cord (17.8 vs 7.2 p = 0.02. Moreover the maximum dose to the spinal cord was lower with IMRT (30.2 vs 19.9, p Conclusions In HL male patients IMRT seems feasible and accurate while for women HL patients IMRT should be used with caution.

  17. Comparing four volumetric modulated arc therapy beam arrangements for the treatment of early-stage prostate cancer

    Science.gov (United States)

    Elith, Craig A; Dempsey, Shane E; Warren-Forward, Helen M

    2014-01-01

    Introduction This study compared four different volumetric modulated arc therapy (VMAT) beam arrangements for the treatment of early-stage prostate cancer examining plan quality and the impact on a radiotherapy department's resources. Methods Twenty prostate cases were retrospectively planned using four VMAT beam arrangements (1) a partial arc (PA), (2) one arc (1A), (3) one arc plus a partial arc (1A + PA) and (4) two arcs (2A). The quality of the dose distributions generated were compared by examining the overall plan quality, the homogeneity and conformity to the planning target volume (PTV), the number of monitor units and the dose delivered to the organs at risk. Departmental resources were considered by recording the planning time and beam delivery time. Results Each technique produced a plan of similar quality that was considered adequate for treatment; though some differences were noted. The 1A, 1A + PA and 2A plans demonstrated a better conformity to the PTV which correlated to improved sparing of the rectum in the 60–70 Gy range for the 1A + PA and 2A techniques. The time needed to generate the plans was different for each technique ranging from 13.1 min for 1A + PA to 17.8 min for 1A. The PA beam delivery time was fastest with a mean time of 0.9 min. Beam-on times then increased with an increase in the number of arcs up to an average of 2.2 min for the 2A technique. Conclusion Which VMAT technique is best suited for clinical implementation for the treatment of prostate cancer may be dictated by the individual patient and the availability of departmental resources. PMID:26229643

  18. Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human Mesenchymal Stem Cells: Involvement of HIF-1α, FASN, and mTORC1.

    Science.gov (United States)

    Lee, Hyun Jik; Ryu, Jung Min; Jung, Young Hyun; Oh, Sang Yub; Lee, Sei-Jung; Han, Ho Jae

    2015-07-01

    The control of stem cells by oxygen signaling is an important way to improve various stem cell physiological functions and metabolic nutrient alteration. Lipid metabolism alteration via hypoxia is thought to be a key factor in controlling stem cell fate and function. However, the interaction between hypoxia and the metabolic and functional changes to stem cells is incompletely described. This study aimed to identify hypoxia-inducible lipid metabolic enzymes that can regulate umbilical cord blood (UCB)-derived human mesenchymal stem cell (hMSC) proliferation and migration and to demonstrate the signaling pathway that controls functional change in UCB-hMSCs. Our results indicate that hypoxia treatment stimulates UCB-hMSC proliferation, and expression of two lipogenic enzymes: fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1). FASN but not SCD1 is a key enzyme for regulation of UCB-hMSC proliferation and migration. Hypoxia-induced FASN expression was controlled by the hypoxia-inducible factor-1 alpha (HIF-1α)/SCAP/SREBP1 pathway. Mammalian target of rapamycin (mTOR) was phosphorylated by hypoxia, whereas inhibition of FASN by cerulenin suppressed hypoxia-induced mTOR phosphorylation as well as UCB-hMSC proliferation and migration. RAPTOR small interfering RNA transfection significantly inhibited hypoxia-induced proliferation and migration. Hypoxia-induced mTOR also regulated CDK2, CDK4, cyclin D1, cyclin E, and F-actin expression as well as that of c-myc, p-cofilin, profilin, and Rho GTPase. Taken together, the results suggest that mTORC1 mainly regulates UCB-hMSC proliferation and migration under hypoxia conditions via control of cell cycle and F-actin organization modulating factors. In conclusion, the HIF-1α/FASN/mTORC1 axis is a key pathway linking hypoxia-induced lipid metabolism with proliferation and migration in UCB-hMSCs. Stem Cells 2015;33:2182-2195.

  19. Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

    Directory of Open Access Journals (Sweden)

    Nicolas Martin

    Full Text Available Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence. We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

  20. Advances of Hypoxia and Lung Cancer

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    Xuebing LI

    2013-04-01

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

  1. Dosimetric and radiobiological comparison of Forward Tangent Intensity Modulated Radiation Therapy (FT-IMRT) and Volumetric Modulated Arc Therapy (VMAT) for early stage whole breast cancer

    Science.gov (United States)

    Moshiri Sedeh, Nader

    Intensity Modulated Radiation Therapy (IMRT) is a well-known type of external beam radiation therapy. The advancement in technology has had an inevitable influence in radiation oncology as well that has led to a newer and faster dose delivery technique called Volumetric Modulated Arc Therapy (VMAT). Since the presence of the VMAT modality in clinics in the late 2000, there have been many studies in order to compare the results of the VMAT modality with the current popular modality IMRT for various tumor sites in the body such as brain, prostate, head and neck, cervix and anal carcinoma. This is the first study to compare VMAT with IMRT for breast cancer. The results show that the RapidArc technique in Eclipse version 11 does not improve all aspects of the treatment plans for the breast cases automatically and easily, but it needs to be manipulated by extra techniques to create acceptable plans thus further research is needed.

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

    Science.gov (United States)

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

    2014-09-01

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

  3. Effect of calcitonin gene related peptide regulated nuclear factor kappa B signal transduction on c-kit+ cardiac stem cells in hypoxia state

    Directory of Open Access Journals (Sweden)

    Xian-ping LONG

    2015-11-01

    Full Text Available Objective To investigate the effects of calcitonin gene-related peptide (CGRP on the apoptosis of c-kit+ cardiac stem cells in hypoxia. Methods Ischemia and hypoxia models of c-kit+ cardiac stem cells were reproduced in vitro. The models were divided into hypoxia+CGRP group, hypoxia+CGRP8-37 (antagonist of CGRP group, hypoxia control group, normal oxygen group, and hypoxia+BAY11-7082 [antagonist of nuclear factor kappa B (NF-κB] group. NF-κB translocation after hypoxia was detected by immunofluorescence, and NF-κB channel proteins were determined with Western blotting. The NF-κB translocation and the expression of NF-κB channel proteins after CGRP intervention were detected, and the cell apoptosis rate after intervention was determined with flow cytometry in each group. Results Under hypoxia the NF-κB signal pathway was activated, and nuclear translocation occurred in NF-κBP65 (red fluorescence. Compared with hypoxia control group, the expressions of NF-κB related proteins such as P-I-κB, NF-κBP65 and NF-κBP50 decreased obviously (P<0.05. Compared with the hypoxia+CGRP group, the expressions of NF-κB related proteins increased significantly (P<0.05 as mentioned above in hypoxia+CGRP8-37 group. Both the early and late apoptotic rates declined in hypoxia+CGRP group compared with that of hypoxia control group (P<0.05, however, the early apoptotic rate increased markedly in hypoxia+CGRP8-37 group as compared with that of hypoxia+CGRP group (P<0.05. Conclusion Under hypoxia, CGRP may regulate the NF-κB signal pathway, and at the same time suppress the apoptosis of c-kit+ cardiac stem cells. DOI: 10.11855/j.issn.0577-7402.2015.10.03

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

    Directory of Open Access Journals (Sweden)

    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

  5. Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia.

    Science.gov (United States)

    López-Barneo, José; González-Rodríguez, Patricia; Gao, Lin; Fernández-Agüera, M Carmen; Pardal, Ricardo; Ortega-Sáenz, Patricia

    2016-04-15

    Oxygen (O2) is fundamental for cell and whole-body homeostasis. Our understanding of the adaptive processes that take place in response to a lack of O2(hypoxia) has progressed significantly in recent years. The carotid body (CB) is the main arterial chemoreceptor that mediates the acute cardiorespiratory reflexes (hyperventilation and sympathetic activation) triggered by hypoxia. The CB is composed of clusters of cells (glomeruli) in close contact with blood vessels and nerve fibers. Glomus cells, the O2-sensitive elements in the CB, are neuron-like cells that contain O2-sensitive K(+)channels, which are inhibited by hypoxia. This leads to cell depolarization, Ca(2+)entry, and the release of transmitters to activate sensory fibers terminating at the respiratory center. The mechanism whereby O2modulates K(+)channels has remained elusive, although several appealing hypotheses have been postulated. Recent data suggest that mitochondria complex I signaling to membrane K(+)channels plays a fundamental role in acute O2sensing. CB activation during exposure to low Po2is also necessary for acclimatization to chronic hypoxia. CB growth during sustained hypoxia depends on the activation of a resident population of stem cells, which are also activated by transmitters released from the O2-sensitive glomus cells. These advances should foster further studies on the role of CB dysfunction in the pathogenesis of highly prevalent human diseases.

  6. Hypoxia progressively lowers thermal gaping thresholds in bearded dragons, Pogona vitticeps.

    Science.gov (United States)

    Tattersall, Glenn J; Gerlach, Rebecca M

    2005-09-01

    Most animals, including reptiles, lower body temperature (Tb) under hypoxic conditions. Numerous physiological and behavioural traits significant to the regulation of Tb are altered by hypoxia in ways that suggest an orchestrated adjustment of Tb at a new and lower regulated level. We examined this matter in bearded dragons, Pogona vitticeps, a species of reptile that naturally exhibits open mouth gaping at high temperatures, presumably in order to promote evaporation and thus prevent or avoid further increases in Tb. The threshold for the onset of gaping (assessed as the temperature at which lizards spent 50% of their time gaping) was reduced from 36.9 degrees C in normoxia to 35.5 degrees C at 10% and 34.3 degrees C at 6% O2. The overall magnitude or degree of gaping, measured qualitatively, was more pronounced at lower temperatures in hypoxia. Females consistently had lower gaping threshold temperatures than did males, and this difference was retained throughout exposure to hypoxia. In addition to gaping, evaporative water loss from the cloaca may also play a significant role in temperature regulation, since the ambient temperature at which cloacal discharge occurred was also reduced significantly in hypoxia. The results reported herein strongly support the view that hypoxia reduces temperature set-point in lizards and that such changes are coordinated by specific behavioural thermoeffectors that modulate evaporative water loss and thus facilitate a high potential for controlling or modifying Tb.

  7. Chronic intermittent hypoxia preserves bone density in a mouse model of sleep apnea.

    Science.gov (United States)

    Torres, Marta; Montserrat, Josep M; Pavía, Javier; Dalmases, Mireia; Ros, Domenec; Fernandez, Yolanda; Barbé, Ferran; Navajas, Daniel; Farré, Ramon

    2013-12-01

    Very recent clinical research has investigated whether obstructive sleep apnea (OSA) may modulate bone homeostasis but the few data available are conflicting. Here we report novel data obtained in a mouse study specifically designed to determine whether chronic intermittent hypoxia realistically mimicking OSA modifies bone mineral density (BMD). Normal male and female mice and orchidectomized mice (N=10 each group) were subjected to a pattern of high-frequency intermittent hypoxia (20s at 5% and 40s at 21%, 60 cycles/h) for 6h/day. Identical groups breathing room air (normoxia) were the controls. After 32 days of intermittent hypoxia/normoxia the trabecular bone mineral density (BMD) in the peripheral femora were measured by micro-CT scanning. When compared with normoxia (two-way ANOVA), intermittent hypoxia did not significantly modify BMD in the three animal groups tested. Data in this study suggest that the type of intermittent hypoxia characterizing OSA, applied as a single challenge, preserves bone homeostasis.

  8. The effect of hypoxia on facial shape variation and disease phenotypes in chicken embryos

    Directory of Open Access Journals (Sweden)

    Francis Smith

    2013-07-01

    Craniofacial anomalies can arise from both genetic and environmental factors, including prenatal hypoxia. Recent clinical evidence correlates hypoxia to craniofacial malformations. However, the mechanisms by which hypoxia mediates these defects are not yet understood. We examined the cellular mechanisms underlying malformations induced by hypoxia using a chicken (Gallus gallus embryo model. Eggs were incubated in either hypoxic (7, 9, 11, 13, 15, 17 or 19% O2 or normoxic (21% O2 conditions. Embryos were photographed for morphological analysis at days 3–6. For analysis of skeletal development, 13-day embryos were cleared and stained with alcian blue and alizarin red for cartilage and bone, respectively. Quantitative analysis of facial shape variation was performed on images of embryos via geometric morphometrics. Early-stage embryos (day 2 were analyzed for apoptosis via whole-mount and section TUNEL staining and immunostaining for cleaved caspase-3, whereas later-stage embryos (days 4–6 were sectioned in paraffin for analysis of cell proliferation (BrdU, apoptosis (TUNEL and metabolic stress (phospho-AMPK. Results demonstrate that survival is reduced in a dose-dependent manner. Hypoxic embryos displayed a spectrum of craniofacial anomalies, from mild asymmetry and eye defects to more severe frontonasal and cephalic anomalies. Skull bone development was delayed in hypoxic embryos, with some skeletal defects observed. Morphometric analysis showed facial shape variation relative to centroid size and age in hypoxic groups. Hypoxia disrupted cell proliferation and, in early-stage embryos, caused apoptosis of neural crest progenitor cells. Hypoxic embryos also displayed an increased metabolic stress response. These results indicate that hypoxia during early embryonic craniofacial development might induce cellular oxidative stress, leading to apoptosis of the neural crest progenitor cells that are crucial to normal craniofacial morphogenesis.

  9. Clinical Significance of Fetal Cerebroplacental Ratio Combined with Cardiac Monitoring in Early Diagnosis of Fetal Intrauterine Hypoxia%脑-胎盘率与胎心监护联合应用对早期诊断胎儿宫内缺氧的临床意义

    Institute of Scientific and Technical Information of China (English)

    杨辉; 王丽英; 姚姗姗

    2016-01-01

    目的:探讨胎儿的脑-胎盘率与胎心监护联合应用对早期诊断胎儿宫内缺氧的临床意义。方法运用彩色多普勒超声检测该院2013年8月—2015年10月收治并分娩的185例孕34~41周的胎儿脐动脉(UA)和大脑中动脉(MCA)血流的搏动指数(PI)计算脑-胎盘率(PIMCA/PIUA),同时进行胎心监护检查,根据结果分为4组:A组为脑-胎盘率及胎心监护均正常;B组为脑-胎盘率正常,胎心监护异常;C组为脑-胎盘率异常,胎心监护正常;D组为脑-胎盘率及胎心监护均异常。对各组的胎儿宫内缺氧率以及新生儿Apgar评分、脐血血气等宫内缺氧指标进行比较。结果 A组胎儿正常比率(98.6%)明显高于其他3个组(83.3%、82.4%、33.3%),差异有统计学意义(P0.05)。结论脑-胎盘率与胎心监护联合应用对早期诊断胎儿宫内缺氧中起着非常重要的作用,弥补单一方法的不足,提高了诊断的准确性,具有重要的临床意义。%Objective To explore the clinical significance of cerebro-placenta ratio combined with cardiac monitoring in early diagnosis of fetal intrauterine hypoxia. Methods Color doppler ultrasound was used to obtain the blood flow pulsation index(PI) of fetal umbilical artery(UA) and middle cerebral artery (MCA) of 185 cases of 34 ~ 41 weeks of pregnant women enrolled in our hospital from the August of 2013 to the October of 2015. The cerebro-placenta ratio was calculated and the cardiac monitoring inspections was performed at the same time. According to the results, four groups were divided: group A with both normal cerebro-placenta ratio and cardiac monitoring; group B with normal cerebro-placenta ratio and abnormal cardiac monitoring; group C with abnormal cerebro-placenta ratio and normal cardiac monitoring; group D with both abnor-mal cerebro-placenta ratio and cardiac monitoring. And the rates of fetal intrauterine hypoxia and other indexes

  10. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

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

  11. Dose prescription and treatment planning based on FMISO-PET hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Toma-Dasu, Iuliana; Antonovic, Laura (Medical Radiation Physics, Stockholm Univ. and Karolinska Institutet, Stockholm (Sweden)), E-mail: iuliana.livia.dasu@ki.se; Uhrdin, Johan (RaySearch Laboratories AB, Stockholm (Sweden)); Dasu, Alexandru (Dept. of Radiation Physics UHL, County Council of Oestergoetland, Linkoeping (Sweden); Radiation Physics, Dept. of Medical and Health Sciences, Faculty of Health Sciences, Linkoeping Univ., Linkoeping (Sweden)); Nuyts, Sandra; Dirix, Piet; Haustermans, Karin (Leuven Univ. Hospitals, Gasthuisberg, Dept. of Radiotherapy, Leuven (Belgium)); Brahme, Anders (Dept. of Oncology and Pathology, Karolinska Institutet, Stockholm (Sweden))

    2012-02-15

    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

  12. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Oliwia Alicja Janc

    2014-02-01

    Full Text Available Rett syndrome (RS causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2-/y hippocampus, confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3-5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved short-term plasticity, and fully restored synaptic long-term potentiation. Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

  13. The role of necrosis, acute hypoxia and chronic hypoxia in 18F-FMISO PET image contrast: a computational modelling study

    Science.gov (United States)

    Warren, Daniel R.; Partridge, Mike

    2016-12-01

    Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ({{P}{{\\text{O}2}}} ) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 μm versus  ˜4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (˜20 min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of {{P}{{\\text{O}2}}} and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local {{P}{{\\text{O}2}}} of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue {{P}{{\\text{O}2}}} : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at  ˜5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing

  14. Influence of hypoxia and hypercapnia on sleep state-dependent heart rate variability behavior in newborn lambs.

    Science.gov (United States)

    Beuchée, Alain; Hernández, Alfredo I; Duvareille, Charles; Daniel, David; Samson, Nathalie; Pladys, Patrick; Praud, Jean-Paul

    2012-11-01

    Although hypercapnia and/or hypoxia are frequently present during chronic lung disease of infancy and have also been implicated in sudden infant death syndrome (SIDS), their effect on cardiac autonomic regulation remains unclear. The authors' goal is to test that hypercapnia and hypoxia alter sleep-wake cycle-dependent heart rate variability (HRV) in the neonatal period. Experimental study measuring HRV during sleep states in lambs randomly exposed to hypercapnia, hypoxia, or air. University center for perinatal research in ovines (Sherbrooke, Canada). INSERM-university research unit for signal processing (Rennes, France). Six nonsedated, full-term lambs. Each lamb underwent polysomnographic recordings while in a chamber flowed with either air or 21% O(2) + 5% CO(2) (hypercapnia) or 10% O(2) + 0% CO(2) (hypoxia) on day 3, 4, and 5 of postnatal age. Hypercapnia increased the time spent in wakefulness and hypoxia the time spent in quiet sleep (QS). The state of alertness was the major determinant of HRV characterized with linear or nonlinear methods. Compared with QS, active sleep (AS) was associated with an overall increase in HRV magnitude and short-term self-similarity and a decrease in entropy of cardiac cycle length in air. This AS-related HRV pattern persisted in hypercapnia and was even more pronounced in hypoxia. Enhancement of AS-related sympathovagal coactivation in hypoxia, together with increased heart rate regularity, may be evidence that AS + hypoxia represent a particularly vulnerable state in early life. This should be kept in mind when deciding the optimal arterial oxygenation target in newborns and when investigating the potential involvement of hypoxia in SIDS pathogenesis.

  15. Anti-inflammatory effects of tetrahydrobiopterin on early rejection in renal allografts : modulation of inducible nitric oxide synthase

    NARCIS (Netherlands)

    Huisman, A; Vos, [No Value; van Faassen, EE; Joles, JA; Grone, HJ; Martasek, P; van Zonneveld, AJ; Vanin, AF; Rabelink, TJ

    2002-01-01

    Oxidative stress contributes to the development of early transplant failure. As nitric oxide synthases (NOS) can act as sources of superoxide, we investigated the effect of the NOS cofactor tetrahydrobiopterin (BH4) on oxyradical production and early rejection in a rat kidney transplantation model.

  16. Hypoxia-inducible genes encoding small EF-hand proteins in rice and tomato.

    Science.gov (United States)

    Otsuka, Chie; Minami, Ikuko; Oda, Kenji

    2010-01-01

    Rice has evolved metabolic and morphological adaptations to low-oxygen stress to grow in submerged paddy fields. To characterize the molecular components that mediate the response to hypoxia in rice, we identified low-oxygen stress early response genes by microarray analysis. Among the highly responsive genes, five genes, OsHREF1 to OsHREF5, shared strong homology. They encoded small proteins harboring two EF-hands, typical Ca(2+)-binding motifs. Homologous genes were found in many land plants, including SlHREF in tomato, which is also strongly induced by hypoxia. SlHREF induction was detected in both roots and shoots of tomato plants under hypoxia. With the exception of OsHREF5, OsHREF expression was unaffected by drought, salinity, cold, or osmotic stress. Fluorescent signals of green fluorescent protein-fused OsHREFs were detected in the cytosol and nucleus. Ruthenium red, an inhibitor of intracellular Ca(2+) release, repressed induction of OsHREF1-4 under hypoxia. The HREFs may be related to the Ca(2+) response to hypoxia.

  17. Natural chemical tags reveal trophic resilience of demersal fish to hypoxia exposure

    Science.gov (United States)

    Mohan, J. A.; Walther, B. D.

    2016-02-01

    Seasonal hypoxia may affect benthic ecosystems by altering trophic relationships between benthic prey and mobile predators. Identifying the sublethal effects of hypoxia on mobile fishes is difficult without long-term chronological geochemical records of individual exposure histories. In this study, trace element profiles in otoliths of demersal Atlantic croaker Micropogonias undulatus collected from the "Dead Zone" region of the northern Gulf of Mexico were used to quantify environmental exposure histories over the 2-3 months prior to capture. Otoliths were analyzed to quantify profiles of manganese (Mn) as a proxy of redox conditions and barium (Ba) as a proxy of estuarine habitat use. Estuarine and hypoxia exposure indices based on these proxies clustered fish into four recent exposure groups that included: late estuarine migrants, early estuarine migrants, normoxic coastal residents, and hypoxic coastal resident fish. Muscle tissue stable isotope values of carbon and nitrogen that also reflected 2-3 months of recent dietary history were used to estimate isotope niche area using standard ellipses. Fish demonstrating more estuarine habitat use displayed larger niche areas, while normoxic and hypoxic coastal resident fish exhibited small and statistically similar niche areas. These results suggest trophic resilience of demersal croaker to seasonal hypoxia in the northern Gulf of Mexico. A combination of otolith chemistry and tissue stable isotopes further enhances our understanding of responses to sublethal hypoxia and the potential consequences for ecosystem functioning.

  18. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  19. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  20. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  1. 2006 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  2. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  3. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  4. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

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

  5. Measuring and monitoring eutrophication and hypoxia

    Digital Repository Service at National Institute of Oceanography (India)

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

    Coastal hypoxia is a complex problem and, although research has made great strides in understanding its causes and remedies, more knowledge is needed to fill critical gaps that impede action. To establish long-term trends and identify changes...

  6. Triptolide protects astrocytes from hypoxia/ reoxygenation injury

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  7. Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats.

    Science.gov (United States)

    Redrobe, John P; Elster, Lisbeth; Frederiksen, Kristen; Bundgaard, Christoffer; de Jong, Inge E M; Smith, Garrick P; Bruun, Anne Techau; Larsen, Peter H; Didriksen, Michael

    2012-06-01

    A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals. The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively. In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABA(A) α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats. Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.

  8. Resveratrol has inhibitory effects on the hypoxia-induced inflammation and angiogenesis in human adipose tissue in vitro.

    Science.gov (United States)

    Cullberg, Karina B; Olholm, Jens; Paulsen, Søren K; Foldager, Casper B; Lind, Martin; Richelsen, Bjørn; Pedersen, Steen B

    2013-05-13

    Hypoxia modulates the production of proteins involved in e.g. inflammation, angiogenesis and glucose utilization and hypoxia may therefore be an important factor underlying adipose tissue dysfunction in obesity. Resveratrol (RSV) is a natural polyphenolic compound and has been shown to have powerful anti-inflammatory effects and beneficial effects on several obesity-related complications. Thus, in the present study we investigated whether RSV has effects on hypoxic markers (GLUT-1, VEGF), hypoxia-induced key markers of inflammation (IL8, IL6), and leptin in human adipose tissue in vitro. Hypoxia was induced by incubating human adipose tissue fragments with 1% O2 for 24h as compared to 21% O2 The gene expressions were investigated by RT-PCR and protein release by Elisa. Hypoxia increases the expression of glucose transporter-1 (GLUT-1) (19-fold, pleptin (9-fold). The protein levels of VEGF released to the medium was increased (8-fold, padipose tissue in the expression and release of inflammation and angiogenesis-related adipokines. In addition the inhibition of hypoxia-mediated inflammation and angiogenesis might represent a novel mechanism of RSV in preventing obesity-related pathologies. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Molecular mechanisms underlying synergistic adhesion of sickle red blood cells by hypoxia and low nitric oxide bioavailability.

    Science.gov (United States)

    Gutsaeva, Diana R; Montero-Huerta, Pedro; Parkerson, James B; Yerigenahally, Shobha D; Ikuta, Tohru; Head, C Alvin

    2014-03-20

    The molecular mechanisms by which nitric oxide (NO) bioavailability modulates the clinical expression of sickle cell disease (SCD) remain elusive. We investigated the effect of hypoxia and NO bioavailability on sickle red blood cell (sRBC) adhesion using mice deficient for endothelial NO synthase (eNOS) because their NO metabolite levels are similar to those of SCD mice but without hypoxemia. Whereas sRBC adhesion to endothelial cells in eNOS-deficient mice was synergistically upregulated at the onset of hypoxia, leukocyte adhesion was unaffected. Restoring NO metabolite levels to physiological levels markedly reduced sRBC adhesion to levels seen under normoxia. These results indicate that sRBC adherence to endothelial cells increases in response to hypoxia prior to leukocyte adherence, and that low NO bioavailability synergistically upregulates sRBC adhesion under hypoxia. Although multiple adhesion molecules mediate sRBC adhesion, we found a central role for P-selectin in sRBC adhesion. Hypoxia and low NO bioavailability upregulated P-selectin expression in endothelial cells in an additive manner through p38 kinase pathways. These results demonstrate novel cellular and signaling mechanisms that regulate sRBC adhesion under hypoxia and low NO bioavailability. Importantly, these findings point us toward new molecular targets to inhibit cell adhesion in SCD.

  10. Sensing and surviving hypoxia in vertebrates.

    Science.gov (United States)

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

    2016-02-01

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

  11. Nox2 and Cyclosporine-Induced Renal Hypoxia.

    Science.gov (United States)

    Djamali, Arjang; Wilson, Nancy A; Sadowski, Elizabeth A; Zha, Wei; Niles, David; Hafez, Omeed; Dorn, Justin R; Mehner, Thomas R; Grimm, Paul C; Hoffmann, F Michael; Zhong, Weixiong; Fain, Sean B; Reese, Shannon R

    2016-06-01

    We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.

  12. 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

  13. Hypoxia diminishes the detoxification of the environmental mutagen benzo[a]pyrene.

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    Schults, Marten A; Sanen, Kathleen; Godschalk, Roger W; Theys, Jan; van Schooten, Frederik J; Chiu, Roland K

    2014-11-01

    Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIFα can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elucidate the mechanism behind the ability of hypoxia to increase mutagenicity of carcinogens, we examined the activation and detoxification of BaP under hypoxic conditions. To this end, the human lung carcinoma cell line A549 was treated with BaP under 20%, 5% or 0.2% oxygen for 18h and alterations in BaP metabolism were assayed. First, BaP-induced expression of key metabolic enzymes was analysed; expression levels of the activating CYP1A1 and CYP1B1 were increased, while the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. To evaluate whether these changes had an effect on metabolism, levels of BaP and several of its metabolites were determined. Cells under hypoxia have a reduced capacity to metabolise BaP leaving more of the parent molecule intact. Additionally, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations. Finally, under hypoxia, DNA adducts accumulated over a period of 168 h, whereas adducts were efficiently removed in 20% oxygen conditions. The delayed detoxification kinetics resulted in a 1.5-fold increase in DNA adducts. These data indicate that the metabolism under hypoxic conditions has shifted towards increased activation of BaP instead of detoxification and support the idea that modulation of carcinogen metabolism is an important additional mechanism for the observed HIF1 mediated genetic instability.

  14. Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer.

    Science.gov (United States)

    Lei, Jianjun; Fan, Lin; Wei, Guangbing; Chen, Xin; Duan, Wanxing; Xu, Qinhong; Sheng, Wei; Wang, Kang; Li, Xuqi

    2015-04-01

    Hypoxia can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, their mechanisms remain unclear. The objective of this study was to evaluate the role of Gli-1, an effector of the Hedgehog pathway, in the hypoxia-induced EMT and invasion of breast cancer cells. Human breast cancer MDA-MB-231 cells were transfected with HIF-1α or Gli-1-specific small interfering RNA (siRNA) and cultured under a normoxic or hypoxic condition. The relative levels of HIF-1α, Gli-1, E-cadherin, and vimentin in the cells were characterized by quantitative RT-PCR and Western blot assays, and the invasion of MDA-MB-231 cells was determined. Data was analyzed by Student T test, one-way ANOVA, and post hoc LSD test or Mann-Whitney U when applicable. We observed that hypoxia significantly upregulated the relative levels of vimentin expression, but downregulated E-cadherin expression and promoted the invasion of MDA-MB-231 cells, associated with upregulated HIF-1α translation and Gil-1 expression. Knockdown of HIF-1α mitigated hypoxia-modulated Gil-1, vimentin and E-cadherin expression, and invasion of MDA-MB-231 cells. Knockdown of Gil-1 did not significantly change hypoxia-upregulated HIF-1α translation but completely eliminated hypoxia-modulated vimentin and E-cadherin expression and invasion of MDA-MB-231 cells. These data indicate that Gil-1 is crucial for hypoxia-induced EMT and invasion of breast cancer cells and may be a therapeutic target for intervention of breast cancer metastasis.

  15. Dopamine transporters are involved in the onset of hypoxia-induced dopamine efflux in striatum as revealed by in vivo microdialysis.

    Science.gov (United States)

    Orset, Cyrille; Parrot, Sandrine; Sauvinet, Valérie; Cottet-Emard, Jean-Marie; Bérod, Anne; Pequignot, Jean-Marc; Denoroy, Luc

    2005-06-01

    Although many studies have revealed alterations in neurotransmission during ischaemia, few works have been devoted to the neurochemical effects of mild hypoxia, a situation encountered during life in altitude or in several pathologies. In that context, the present work was undertaken to determine the in vivo mechanisms underlying the striatal dopamine efflux induced by mild hypoxaemic hypoxia. For that purpose, the extracellular concentrations of dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid were simultaneously measured using brain microdialysis during acute hypoxic exposure (10% O(2), 1h) in awake rats. Hypoxia induced a +80% increase in dopamine. Application of the dopamine transporters inhibitor, nomifensine (10 microM), just before the hypoxia prevented the rise in dopamine during the early part of hypoxia; in contrast the application of nomifensine after the beginning of hypoxia, failed to alter the increase in dopamine. Application of the voltage-dependent Na(+) channel blocker tetrodotoxin abolished the increase in dopamine, whether administered just before or after the beginning of hypoxia. These data show that the neurochemical mechanisms of the dopamine efflux may change over the course of the hypoxic exposure, dopamine transporters being involved only at the beginning of hypoxia.

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

    Science.gov (United States)

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

    2012-05-15

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

  17. Circulating MicroRNAs in maternal blood as potential biomarkers for fetal hypoxia in-utero.

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    Clare L Whitehead

    Full Text Available Stillbirth affects 1 in 200 pregnancies and commonly arises due to a lack of oxygen supply to the fetus. Current tests to detect fetal hypoxia in-utero lack the sensitivity to identify many babies at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may serve as non-invasive biomarkers for pregnancy complications. In this study, we examined the expression of miRs known to be regulated by hypoxia in two clinical settings of significant fetal hypoxia: 1 labour and 2 fetal growth restriction. Six miRs (miR 210, miR 21, miR 424, miR 199a, miR 20b, and miR 373 were differentially expressed in pregnancies complicated by fetal hypoxia. In healthy term pregnancies there was a 4.2 fold increase in miR 210 (p<0.01, 2.7 fold increase in miR 424 (p<0.05, 2.6 fold increase in miR 199a (p<0.01 and 2.3 fold increase in miR 20b (p<0.05 from prior to labour to delivery of the fetus. Furthermore, the combined expression of miR 21 and miR 20b correlated with the degree of fetal hypoxia at birth determined by umbilical cord lactate delivery (r = 0.79, p = 0.03. In pregnancies complicated by severe preterm fetal growth restriction there was upregulation of the hypoxia-regulated miRs compared to gestation-matched controls: 3.6 fold in miR 210 (p<0.01, 3.6 fold in miR 424 (p<0.05, 5.9 fold in miR 21 (p<0.01, 3.8 fold in miR 199a (p<0.01 and 3.7 fold in miR 20b (p<0.01. Interestingly, the expression of miR 373 in gestation matched controls was very low, but was very highly expressed in FGR (p<0.0001. Furthermore, the expression increased in keeping with the degree of in-utero hypoxia estimated by fetal Doppler velocimetry. We conclude quantifying hypoxia-regulated miRs in the maternal blood may identify pregnancies at risk of fetal hypoxia, enabling early intervention to improve perinatal outcomes.

  18. Maternal high-fat diet modulates hepatic glucose, lipid homeostasis and gene expression in the PPAR pathway in the early life of offspring.

    Science.gov (United States)

    Zheng, Jia; Xiao, Xinhua; Zhang, Qian; Yu, Miao; Xu, Jianping; Wang, Zhixin

    2014-08-25

    Maternal dietary modifications determine the susceptibility to metabolic diseases in adult life. However, whether maternal high-fat feeding can modulate glucose and lipid metabolism in the early life of offspring is less understood. Furthermore, we explored the underlying mechanisms that influence the phenotype. Using C57BL/6J mice, we examined the effects on the offspring at weaning from dams fed with a high-fat diet or normal chow diet throughout pregnancy and lactation. Gene array experiments and quantitative real-time PCR were performed in the liver tissues of the offspring mice. The offspring of the dams fed the high-fat diet had a heavier body weight, impaired glucose tolerance, decreased insulin sensitivity, increased serum cholesterol and hepatic steatosis at weaning. Bioinformatic analyses indicated that all differentially expressed genes of the offspring between the two groups were mapped to nine pathways. Genes in the peroxisome proliferator-activated receptor (PPAR) signaling pathway were verified by quantitative real-time PCR and these genes were significantly up-regulated in the high-fat diet offspring. A maternal high-fat diet during pregnancy and lactation can modulate hepatic glucose, lipid homeostasis, and gene expression in the PPAR signaling in the early life of offspring, and our results suggested that potential mechanisms that influences this phenotype may be related partially to up-regulate some gene expression in the PPAR signalling pathway.

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

    Science.gov (United States)

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

    2017-01-01

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

  20. Cerebral hypoxia and ischemia in preterm infants

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    Alberto Ravarino

    2014-06-01

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

  1. Hypoxia and HIFs in regulating the development of the hematopoietic system.

    Science.gov (United States)

    Imanirad, Parisa; Dzierzak, Elaine

    2013-12-01

    Many physiologic processes during the early stages of mammalian ontogeny, particularly placental and vascular development, take place in the low oxygen environment of the uterus. Organogenesis is affected by hypoxia inducible factor (HIF) transcription factors that are sensors of hypoxia. In response to hypoxia, HIFs activate downstream target genes - growth and metabolism factors. During hematopoietic system ontogeny, blood cells and hematopoietic progenitor/stem cells are respectively generated from mesodermal precursors, hemangioblasts, and from a specialized subset of endothelial cells that are hemogenic. Since HIFs are known to play a central role in vascular development, and hematopoietic system development occurs in parallel to that of the vascular system, several studies have examined the role of HIFs in hematopoietic development. The response to hypoxia has been examined in early and mid-gestation mouse embryos through genetic deletion of HIF subunits. We review here the data showing that hematopoietic tissues of the embryo are hypoxic and express HIFs and HIF downstream targets, and that HIFs regulate the development and function of hematopoietic progenitor/stem cells.

  2. Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function.

    Science.gov (United States)

    Baarendse, Petra J J; Counotte, Danielle S; O'Donnell, Patricio; Vanderschuren, Louk J M J

    2013-07-01

    Social experiences during youth are thought to be critical for proper social and cognitive development. Conversely, social insults during development can cause long-lasting behavioral impairments and increase the vulnerability for psychopathology later in life. To investigate the importance of social experience during the juvenile and early adolescent stage for the development of cognitive control capacities, rats were socially isolated from postnatal day 21 to 42 followed by re-socialization until they reached adulthood. Subsequently, two behavioral dimensions of impulsivity (impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task) and decision making (in the rat gambling task) were assessed. In a separate group of animals, long-lasting cellular and synaptic changes in adult medial prefrontal cortex (PFC) pyramidal neurons were determined following social isolation. Juvenile and early adolescent social isolation resulted in impairments in impulsive action and decision making under novel or challenging circumstances. Moreover, socially isolated rats had a reduced response to enhancement of dopaminergic neurotransmission (using amphetamine or GBR12909) in the 5-CSRTT under challenging conditions. Impulsive choice was not affected by social isolation. These behavioral deficits were accompanied by a loss of sensitivity to dopamine of pyramidal neurons in the medial PFC. Our data show long-lasting deleterious effects of early social isolation on cognitive control and its neural substrates. Alterations in prefrontal cognitive control mechanisms may contribute to the enhanced risk for psychiatric disorders induced by aberrations in the early social environment.

  3. The perception of speech modulation cues in lexical tones is guided by early language-specific experience

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    Laurianne eCabrera

    2015-08-01

    Full Text Available A number of studies showed that infants reorganize their perception of speech sounds according to their native language categories during their first year of life. Still, information is lacking about the contribution of basic auditory mechanisms to this process. This study aimed to evaluate when native language experience starts to noticeably affect the perceptual processing of basic acoustic cues (i.e., frequency-modulation (FM and amplitude-modulation (AM information known to be crucial for speech perception in adults. The discrimination of a lexical-tone contrast (rising versus low was assessed in 6- and 10-month-old infants learning either French or Mandarin using a visual habituation paradigm. The lexical tones were presented in two conditions designed to either keep intact or to severely degrade the FM and fine spectral cues needed to accurately perceive voice-pitch trajectory. A third condition was designed to assess the discrimination of the same voice-pitch trajectories using click trains containing only the FM cues related to the fundamental-frequency (F0 in French- and Mandarin-learning 10-month-old infants. Results showed that the younger infants of both language groups and the Mandarin-learning 10-month-olds discriminated the intact lexical-tone contrast while French-learning 10-month-olds failed. However, only the French 10-month-olds discriminated degraded lexical tones when FM, and thus voice-pitch cues were reduced. Moreover, Mandarin-learning 10-month-olds were found to discriminate the pitch trajectories as presented in click trains better than French infants. Altogether, these results reveal that the perceptual reorganization occurring during the first year of life for lexical tones is coupled with changes in the auditory ability to use speech modulation cues.

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

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    L. Zillén

    2010-08-01

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

  5. Cognition and chronic hypoxia in pulmonary diseases

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    Renata Areza-Fegyveres

    Full Text Available Abstract Lung disease with chronic hypoxia has been associated with cognitive impairment of the subcortical type. Objectives: To review the cognitive effects of chronic hypoxia in patients with lung disease and its pathophysiology in brain metabolism. Methods: A literature search of Pubmed data was performed. The words and expressions from the text subitems including "pathophysiology of brain hypoxia", "neuropsychology and hypoxia", "white matter injury and chronic hypoxia", for instance, were key words in a search of reports spanning from 1957 to 2009. Original articles were included. Results: According to national and international literature, patients with chronic obstructive pulmonary disease and sleep obstructive apnea syndrome perform worse on tests of attention, executive functions and mental speed. The severity of pulmonary disease correlates with degree of cognitive impairment. These findings support the diagnosis of subcortical type encephalopathy. Conclusion: Cognitive effects of clinical diseases are given limited importance in congresses and symposia about cognitive impairment and its etiology. Professionals that deal with patients presenting cognitive loss should be aware of the etiologies outlined above as a major cause or potential contributory factors, and of their implications for treatment adherence and quality of life.

  6. Preparation and Preservation of Hypoxia UW Solution

    Institute of Scientific and Technical Information of China (English)

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

    2007-01-01

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

  7. Hypoxia Inhibits Hypertrophic Differentiation and Endochondral Ossification in Explanted Tibiae

    NARCIS (Netherlands)

    Leijten, Jeroen Christianus Hermanus; Moreira Teixeira, Liliana; Landman, Ellie; van Blitterswijk, Clemens; Karperien, Hermanus Bernardus Johannes

    2012-01-01

    Purpose: 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

  8. Autophagy contributes to regulation of the hypoxia response during submergence in Arabidopsis thaliana.

    Science.gov (United States)

    Chen, Liang; Liao, Bin; Qi, Hua; Xie, Li-Juan; Huang, Li; Tan, Wei-Juan; Zhai, Ning; Yuan, Li-Bing; Zhou, Ying; Yu, Lu-Jun; Chen, Qin-Fang; Shu, Wensheng; Xiao, Shi

    2015-01-01

    Autophagy involves massive degradation of intracellular components and functions as a conserved system that helps cells to adapt to adverse conditions. In mammals, hypoxia rapidly stimulates autophagy as a cell survival response. Here, we examine the function of autophagy in the regulation of the plant response to submergence, an abiotic stress that leads to hypoxia and anaerobic respiration in plant cells. In Arabidopsis thaliana, submergence induces the transcription of autophagy-related (ATG) genes and the formation of autophagosomes. Consistent with this, the autophagy-defective (atg) mutants are hypersensitive to submergence stress and treatment with ethanol, the end product of anaerobic respiration. Upon submergence, the atg mutants have increased levels of transcripts of anaerobic respiration genes (alcohol dehydrogenase 1, ADH1 and pyruvate decarboxylase 1, PDC1), but reduced levels of transcripts of other hypoxia- and ethylene-responsive genes. Both submergence and ethanol treatments induce the accumulation of reactive oxygen species (ROS) in the rosettes of atg mutants more than in the wild type. Moreover, the production of ROS by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is necessary for plant tolerance to submergence and ethanol, submergence-induced expression of ADH1 and PDC1, and activation of autophagy. The submergence- and ethanol-sensitive phenotypes in the atg mutants depend on a complete salicylic acid (SA) signaling pathway. Together, our findings demonstrate that submergence-induced autophagy functions in the hypoxia response in Arabidopsis by modulating SA-mediated cellular homeostasis.

  9. Identification of a BMP inhibitor-responsive promoter module required for expression of the early neural gene zic1.

    Science.gov (United States)

    Tropepe, Vincent; Li, Shuhong; Dickinson, Amanda; Gamse, Joshua T; Sive, Hazel L

    2006-01-15

    Expression of the transcription factor zic1 at the onset of gastrulation is one of the earliest molecular indicators of neural fate determination in Xenopus. Inhibition of bone morphogenetic protein (BMP) signaling is critical for activation of zic1 expression and fundamental for establishing neural identity in both vertebrates and invertebrates. The mechanism by which interruption of BMP signaling activates neural-specific gene expression is not understood. Here, we report identification of a 215 bp genomic module that is both necessary and sufficient to activate Xenopus zic1 transcription upon interruption of BMP signaling. Transgenic analyses demonstrate that this BMP inhibitory response module (BIRM) is required for expression in the whole embryo. Multiple consensus binding sites for specific transcription factor families within the BIRM are required for its activity and some of these regions are phylogenetically conserved between orthologous vertebrate zic1 genes. These data suggest that interruption of BMP signaling facilitates neural determination via a complex mechanism, involving multiple regulatory factors that cooperate to control zic1 expression.

  10. Rat reaction to hypokinesia after prior adaptation to hypoxia

    Science.gov (United States)

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

    1980-01-01

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

  11. Buffering and Amplifying Interactions among OAW (Ocean Acidification & Warming) and Nutrient Enrichment on Early Life-Stage Fucus vesiculosus L. (Phaeophyceae) and Their Carry Over Effects to Hypoxia Impact

    Science.gov (United States)

    Al-Janabi, Balsam; Kruse, Inken; Graiff, Angelika; Winde, Vera; Lenz, Mark; Wahl, Martin

    2016-01-01

    Ocean acidification and warming (OAW) are occurring globally. Additionally, at a more local scale the spreading of hypoxic conditions is promoted by eutrophication and warming. In the semi-enclosed brackish Baltic Sea, occasional upwelling in late summer and autumn may expose even shallow-water communities including the macroalga Fucus vesiculosus to particularly acidified, nutrient-rich and oxygen-poor water bodies. During summer 2014 (July–September) sibling groups of early life-stage F. vesiculosus were exposed to OAW in the presence and absence of enhanced nutrient levels and, subsequently to a single upwelling event in a near-natural scenario which included all environmental fluctuations in the Kiel Fjord, southwestern Baltic Sea, Germany (54°27 ´N, 10°11 ´W). We strove to elucidate the single and combined impacts of these potential stressors, and how stress sensitivity varies among genetically different sibling groups. Enhanced by a circumstantial natural heat wave, warming and acidification increased mortalities and reduced growth in F. vesiculosus germlings. This impact, however, was mitigated by enhanced nutrient conditions. Survival under OAW conditions strongly varied among sibling groups hinting at a substantial adaptive potential of the natural Fucus populations in the Western Baltic. A three-day experimental upwelling caused severe mortality of Fucus germlings, which was substantially more severe in those sibling groups which previously had been exposed to OAW. Our results show that global (OAW), regional (nutrient enrichment) and local pressures (upwelling), both alone and co-occurring may have synergistic and antagonistic effects on survival and/or growth of Fucus germlings. This result emphasizes the need to consider combined stress effects. PMID:27043710

  12. Buffering and Amplifying Interactions among OAW (Ocean Acidification & Warming) and Nutrient Enrichment on Early Life-Stage Fucus vesiculosus L. (Phaeophyceae) and Their Carry Over Effects to Hypoxia Impact.

    Science.gov (United States)

    Al-Janabi, Balsam; Kruse, Inken; Graiff, Angelika; Winde, Vera; Lenz, Mark; Wahl, Martin

    2016-01-01

    Ocean acidification and warming (OAW) are occurring globally. Additionally, at a more local scale the spreading of hypoxic conditions is promoted by eutrophication and warming. In the semi-enclosed brackish Baltic Sea, occasional upwelling in late summer and autumn may expose even shallow-water communities including the macroalga Fucus vesiculosus to particularly acidified, nutrient-rich and oxygen-poor water bodies. During summer 2014 (July-September) sibling groups of early life-stage F. vesiculosus were exposed to OAW in the presence and absence of enhanced nutrient levels and, subsequently to a single upwelling event in a near-natural scenario which included all environmental fluctuations in the Kiel Fjord, southwestern Baltic Sea, Germany (54°27 ´N, 10°11 ´W). We strove to elucidate the single and combined impacts of these potential stressors, and how stress sensitivity varies among genetically different sibling groups. Enhanced by a circumstantial natural heat wave, warming and acidification increased mortalities and reduced growth in F. vesiculosus germlings. This impact, however, was mitigated by enhanced nutrient conditions. Survival under OAW conditions strongly varied among sibling groups hinting at a substantial adaptive potential of the natural Fucus populations in the Western Baltic. A three-day experimental upwelling caused severe mortality of Fucus germlings, which was substantially more severe in those sibling groups which previously had been exposed to OAW. Our results show that global (OAW), regional (nutrient enrichment) and local pressures (upwelling), both alone and co-occurring may have synergistic and antagonistic effects on survival and/or growth of Fucus germlings. This result emphasizes the need to consider combined stress effects.

  13. Buffering and Amplifying Interactions among OAW (Ocean Acidification & Warming and Nutrient Enrichment on Early Life-Stage Fucus vesiculosus L. (Phaeophyceae and Their Carry Over Effects to Hypoxia Impact.

    Directory of Open Access Journals (Sweden)

    Balsam Al-Janabi

    Full Text Available Ocean acidification and warming (OAW are occurring globally. Additionally, at a more local scale the spreading of hypoxic conditions is promoted by eutrophication and warming. In the semi-enclosed brackish Baltic Sea, occasional upwelling in late summer and autumn may expose even shallow-water communities including the macroalga Fucus vesiculosus to particularly acidified, nutrient-rich and oxygen-poor water bodies. During summer 2014 (July-September sibling groups of early life-stage F. vesiculosus were exposed to OAW in the presence and absence of enhanced nutrient levels and, subsequently to a single upwelling event in a near-natural scenario which included all environmental fluctuations in the Kiel Fjord, southwestern Baltic Sea, Germany (54°27 ´N, 10°11 ´W. We strove to elucidate the single and combined impacts of these potential stressors, and how stress sensitivity varies among genetically different sibling groups. Enhanced by a circumstantial natural heat wave, warming and acidification increased mortalities and reduced growth in F. vesiculosus germlings. This impact, however, was mitigated by enhanced nutrient conditions. Survival under OAW conditions strongly varied among sibling groups hinting at a substantial adaptive potential of the natural Fucus populations in the Western Baltic. A three-day experimental upwelling caused severe mortality of Fucus germlings, which was substantially more severe in those sibling groups which previously had been exposed to OAW. Our results show that global (OAW, regional (nutrient enrichment and local pressures (upwelling, both alone and co-occurring may have synergistic and antagonistic effects on survival and/or growth of Fucus germlings. This result emphasizes the need to consider combined stress effects.

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

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

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

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

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

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

  16. Protective effect of salidroside on cardiac apoptosis in mice with chronic intermittent hypoxia.

    Science.gov (United States)

    Lai, Mei-Chih; Lin, Jaung-Geng; Pai, Pei-Ying; Lai, Mei-Hsin; Lin, Yueh-Min; Yeh, Yu-Lan; Cheng, Shiu-Min; Liu, Yi-fan; Huang, Chih-Yang; Lee, Shin-Da

    2014-07-01

    The goal of this study is to determine if salidroside has protective effects on hypoxia-induced cardiac widely dispersed apoptosis in mice with severe sleep apnea model. Sixty-four C57BL/6J mice 5-6 months of age were divided into four groups, i.e. Control group (21% O2, 24h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60s, 20% O2 alternating 60s, 8h per day, 8 weeks, n=16); and Hypoxia+S10 and Hypoxia+S 30 groups (Hypoxia for 1st 4 weeks, hypoxia pretreated 10mg/kg and 30 mg/kg salidroside by oral gavage per day for 2nd 4 weeks, n=16 and 16). The excised hearts from four groups were measured by the heart weight index, H&E staining, TUNEL-positive assays and Western blotting. TUNEL-positive apoptotic cells in mice heart were less in Hypoxia+S10 and Hypoxia+S30 than those in the Hypoxia group. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways) were decreased in Hypoxia+S10 and Hypoxia+S30. In the mitochondria pathway, the protein levels of BcLx, Bcl2, and Bid (anti-apoptotic Bcl2 family) in Hypoxia+S10 and Hypoxia+S30 were more than those in Hypoxia. The protein levels of Bax, t-Bid, activated caspase 9, and activated caspase 3 were less in Hypoxia+S10 and Hypoxia+S30 than those in hypoxia. Our findings suggest that salidroside has protective effects on chronic intermittent hypoxia-induced Fas-dependent and mitochondria-dependent apoptotic pathways in mice hearts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Pheochromocytomas: the (pseudo)-hypoxia hypothesis.

    Science.gov (United States)

    Favier, Judith; Gimenez-Roqueplo, Anne-Paule

    2010-12-01

    Hypoxia and pheochromocytoma/paraganglioma have a long common history. Since the description, almost 40 years ago, of an increased incidence of head and neck paragangliomas in chronic hypoxia, discoveries on oxygen-sensing and on hereditary paraganglioma in the beginning of years 2000 provided the proof of concept of a strong link between these neuroendocrine tumors and the hypoxic pathway. It was demonstrated that both SDH and VHL genes mutations lead to the abnormal stabilization and activation of hypoxia-inducible factors, and to the subsequent regulation of multiple target genes, the products of which are implicated in proliferation, apoptosis, angiogenesis, energy metabolism or invasiveness and metastases. Altogether, physiological, genetic, cellular and molecular data collected over years all point to a central role of the hypoxic or pseudohypoxic pathway in pheochromocytoma and paraganglioma tumorigenesis. 2010 Elsevier Ltd. All rights reserved.

  18. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

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

  19. Involvement of endogenous central hydrogen sulfide (H2S) in hypoxia-induced hypothermia in spontaneously hypertensive rats.

    Science.gov (United States)

    Sabino, João Paulo J; Soriano, Renato N; Donatti, Alberto F; Fernandez, Rodrigo Restrepo; Kwiatkoski, Marcelo; Francescato, Heloísa D C; Coimbra, Terezila M; Branco, Luiz G S

    2017-02-01

    Spontaneously hypertensive rats (SHR) display autonomic imbalance and abnormal body temperature (Tb) adjustments. Hydrogen sulfide (H2S) modulates hypoxia-induced hypothermia, but its role in SHR thermoregulation is unknown. We tested the hypothesis that SHR display peculiar thermoregulatory response to hypoxia and that endogenous H2S overproduced in the caudal nucleus of the solitary tract (NTS) of SHR modulates this response. SHR and Wistar rats were microinjected into the fourth ventricle with aminooxyacetate (AOA, H2S-synthezing enzyme inhibitor) or sodium sulfide (Na2S, H2S donor) and exposed to normoxia (21% inspired O2) or hypoxia (10% inspired O2, 30 min). Tb was continuously measured, and H2S production rate was assessed in caudal NTS homogenates. In both groups, AOA, Na2S, or saline (i.e., control; 1 μL) did not affect euthermia. Hypoxia caused similar decreases in Tb in both groups. AOA presented a longer latency to potentiate hypoxic hypothermia in SHR. Caudal NTS H2S production rate was higher in SHR. We suggest that increased bioavailability of H2S in the caudal NTS of SHR enables the adequate modulation of excitability of peripheral chemoreceptor-activated NTS neurons that ultimately induce suppression of brown adipose tissue thermogenesis, thus accounting for the normal hypoxic hypothermia.

  20. Effects of natural and human-induced hypoxia on coastal benthos

    Directory of Open Access Journals (Sweden)

    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

  1. Effects of natural and human-induced hypoxia on coastal benthos

    Directory of Open Access Journals (Sweden)

    L. A. Levin

    2009-04-01

    Full Text Available Coastal hypoxia (<1.42 ml L−1; 62.5 μM; 2 mg L−1, approx. 30% oxygen saturation occurs seasonally in many estuaries, fjords, and along open coasts subject to upwelling or excessive riverine nutrient input, and permanently in some isolated seas and marine basins. Underlying causes of hypoxia include enhanced nutrient input from natural causes (upwelling or anthropogenic origin (eutrophication and reduction of mixing by limited circulation or enhanced stratification; combined these lead to higher surface water production, microbial respiration and eventual oxygen depletion. Advective inputs of low-oxygen waters may initiate or expand hypoxic conditions. Responses of estuarine, enclosed sea, and open shelf 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, thereby providing 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

  2. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP.

    Science.gov (United States)

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A; Sumikawa, Katumi

    2015-02-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.

  3. Comparison of ocular modulation transfer function determined by a ray-tracing aberrometer and a double-pass system in early cataract patients

    Institute of Scientific and Technical Information of China (English)

    Qiao Liya; Wan Xiuhua; Cai Xiaogu; Balamurali Vasudevan; Xiong Ying; Tan Jiaxuan; Guan Zheng

    2014-01-01

    Background The evaluation of retinal image quality in cataract eyes has gained importance and the clinical modulation transfer functions (MTF) can obtained by aberrometer and double pass (DP) system.This study aimed to compare MTF derived from a ray tracing aberrometer and a DP system in eady cataractous and normal eyes.Methods There were 128 subjects with 61 control eyes and 67 eyes with early cataract defined according to the Lens Opacities Classification System Ⅲ.A laser ray-tracing wavefront aberrometer (iTrace) and a double pass (DP) system (OQAS) assessed ocular MTF for 6.0 mm pupil diameters following dilation.Areas under the MTF (AUMTF) and their correlations were analyzed.Stepwise multiple regression analysis assessed factors affecting the differences between iTrace-and OQAS-derived AUMTF for the early cataract group.Results For both early cataract and control groups,iTrace-derived MTFs were higher than OQAS-derived MTFs across a range of spatial frequencies (P <0.01).No significant difference between the two groups occurred for iTrace-derived AUMTF,but the early cataract group had significantly smaller OQAS-derived AUMTF than did the control group (P <0.01).AUMTF determined from both the techniques demonstrated significant correlations with nuclear opacities,higher-order aberrations (HOAs),visual acuity,and contrast sensitivity functions,while the OQAS-derived AUMTF also demonstrated significant correlations with age and cortical opacity grade.The factors significantly affecting the difference between iTrace and OQAS AUMTF were root-mean-squared HOAs (standardized beta coefficient=-0.63,P <0.01) and age (standardized beta coefficient=0.26,P <0.01).Conclusions MTFs determined from a iTrace and a DP system (OQAS) differ significantly in early cataractous and normal subjects.Correlations with visual performance were higher for the DP system.OQAS-derived MTF may be useful as an indicator of visual performance in early cataract eyes.

  4. Transmissible Plasmid Containing Salmonella enterica Heidelberg Isolates Modulate Cytokine Production During Early Stage of Interaction with Intestinal Epithelial Cells.

    Science.gov (United States)

    Gokulan, Kuppan; Khare, Sangeeta; Williams, Katherine; Foley, Steven L

    2016-08-01

    The variation in cytokine production during bacterial invasion of human intestinal epithelial cells (IECs) is a contributing factor for progression of the infection. A few Salmonella enterica Heidelberg strains isolated from poultry products harbor transmissible plasmids (TPs), including those that encode a type-IV secretion system. Earlier, we showed that these TPs are responsible for increased virulence during infection. This study examines the potential role of these TPs in cytokine production in IECs. This study showed that S. Heidelberg strains containing TPs (we refer as virulent strains) caused decreased interleukin (IL)-10 production in IECs after 1 h infection. The virulent strains induced a high level of tumor necrosis factor-α production under identical conditions. The virulent strains of S. Heidelberg also altered the production of IL-2, IL-17, and granulocyte macrophage colony-stimulating factor compared to an avirulent strain. As a part of infection, bacteria cross the epithelial barrier and encounter intestinal macrophages. Hence, we examined the cytotoxic mechanism of strains of S. Heidelberg in macrophages. Scanning electron microscopy showed cell necrosis occurs during the early stage of infection. In conclusion, virulent S. Heidelberg strains were able to modify the host cytokine profile during the early stages of infection and also caused necrosis in macrophages.

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... (10% 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...... by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = -0...

  6. p53 dependent apoptotic cell death induces embryonic malformation in Carassius auratus under chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Paramita Banerjee Sawant

    Full Text Available Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD, leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD, ultimately resulting in significant (p<0.05 embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos.

  7. p53 Dependent Apoptotic Cell Death Induces Embryonic Malformation in Carassius auratus under Chronic Hypoxia

    Science.gov (United States)

    Dasgupta, Subrata; Sawant, Bhawesh T.; Chadha, Narinder K.; Pal, Asim K.

    2014-01-01

    Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD), leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf) and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD), ultimately resulting in significant (p<0.05) embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos. PMID:25068954

  8. Evidence for a role of gibberellins in salicylic acid-modulated early plant responses to abiotic stress in Arabidopsis seeds.

    Science.gov (United States)

    Alonso-Ramírez, Ana; Rodríguez, Dolores; Reyes, David; Jiménez, Jesús Angel; Nicolás, Gregorio; López-Climent, María; Gómez-Cadenas, Aurelio; Nicolás, Carlos

    2009-07-01

    Exogenous application of gibberellic acid (GA(3)) was able to reverse the inhibitory effect of salt, oxidative, and heat stresses in the germination and seedling establishment of Arabidopsis (Arabidopsis thaliana), this effect being accompanied by an increase in salicylic acid (SA) levels, a hormone that in recent years has been implicated in plant responses to abiotic stress. Furthermore, this treatment induced an increase in the expression levels of the isochorismate synthase1 and nonexpressor of PR1 genes, involved in SA biosynthesis and action, respectively. In addition, we proved that transgenic plants overexpressing a gibberellin (GA)-responsive gene from beechnut (Fagus sylvatica), coding for a member of the GA(3) stimulated in Arabidopsis (GASA) family (FsGASA4), showed a reduced GA dependence for growth and improved responses to salt, oxidative, and heat stress at the level of seed germination and seedling establishment. In 35S:FsGASA4 seeds, the improved behavior under abiotic stress was accompanied by an increase in SA endogenous levels. All these data taken together suggest that this GA-responsive gene and exogenous addition of GAs are able to counteract the inhibitory effects of these adverse environmental conditions in seed germination and seedling growth through modulation of SA biosynthesis. Furthermore, this hypothesis is supported by the fact that sid2 mutants, impaired in SA biosynthesis, are more sensitive to salt stress than wild type and are not affected by exogenous application of GA(3).

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

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

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

  10. Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells.

    Science.gov (United States)

    Kim, Dong Hwan; Sung, Bokyung; Kang, Yong Jung; Hwang, Seong Yeon; Kim, Min Jeong; Yoon, Jeong-Hyun; Im, Eunok; Kim, Nam Deuk

    2015-12-01

    The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1α (HIF-1α) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1α protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1α expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1α stability. However, degradation of HIF-1α by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1α by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxia-induced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1α and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer.

  11. Oxygen-Loaded Nanodroplets Effectively Abrogate Hypoxia Dysregulating Effects on Secretion of MMP-9 and TIMP-1 by Human Monocytes

    Directory of Open Access Journals (Sweden)

    Giulia Rossana Gulino

    2015-01-01

    Full Text Available Monocytes play a key role in the inflammatory stage of the healing process. To allow monocyte migration to injured tissues, the balances between secreted matrix metalloproteinases (MMPs and their inhibitors (TIMPs must be finely modulated. However, a reduction of blood supply and local oxygen tension can modify the phenotype of immune cells. Intriguingly, hypoxia might be targeted by new effective oxygenating devices such as 2H,3H-decafluoropentane- (DFP- based oxygen-loaded nanodroplets (OLNs. Here, hypoxia effects on gelatinase/TIMP release from human peripheral monocytes were investigated, and the therapeutic potential of dextran-shelled OLNs was evaluated. Normoxic monocytes constitutively released ~500 ng/mL MMP-9, ~1.3 ng/mL TIMP-1, and ~0.6 ng/mL TIMP-2 proteins. MMP-2 was not detected. After 24 hours, hypoxia significantly altered MMP-9/TIMP-1 balance by reducing MMP-9 and increasing TIMP-1, without affecting TIMP-2 secretion. Interestingly OLNs, not displaying toxicity to human monocytes after cell internalization, effectively counteracted hypoxia, restoring a normoxia-like MMP-9/TIMP-1 ratio. The action of OLNs was specifically dependent on time-sustained oxygen diffusion up to 24 h from their DFP-based core. Therefore, OLNs appear as innovative, nonconventional, cost-effective, and nontoxic therapeutic tools, to be potentially employed to restore the physiological invasive phenotype of immune cells in hypoxia-associated inflammation.

  12. Retinoblastoma protein (Rb) links hypoxia to altered mechanical properties in cancer cells as measured by an optical tweezer.

    Science.gov (United States)

    Khakshour, S; Labrecque, M P; Esmaeilsabzali, H; Lee, F J S; Cox, M E; Park, E J; Beischlag, T V

    2017-08-10

    Hypoxia modulates actin organization via multiple pathways. Analyzing the effect of hypoxia on the biophysical properties of cancer cells is beneficial for studying modulatory signalling pathways by quantifying cytoskeleton rearrangements. We have characterized the biophysical properties of human LNCaP prostate cancer cells that occur in response to loss of the retinoblastoma protein (Rb) under hypoxic stress using an oscillating optical tweezer. Hypoxia and Rb-loss increased cell stiffness in a fashion that was dependent on activation of the extracellular signal-regulated kinase (ERK) and the protein kinase B (AKT)- mammalian target of rapamycin (MTOR) pathways. Pharmacological inhibition of MEK1/2, AKT or MTOR impeded hypoxia-inducible changes in the actin cytoskeleton and inhibited cell migration in Rb-deficient cells conditioned with hypoxia. These results suggest that loss of Rb in transformed hypoxic cancer cells affects MEK1/2-ERK/AKT-MTOR signalling and promotes motility. Thus, the mechanical characterization of cancer cells using an optical tweezer provides an additional technique for cancer diagnosis/prognosis and evaluating therapeutic performance.

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

    LENUS (Irish Health Repository)

    Cronin, Patricia A

    2010-05-21

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

  14. Regulation of Membrane-Type 4 Matrix Metalloproteinase by SLUG Contributes to Hypoxia-Mediated Metastasis

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    Chi-Hung Huang

    2009-12-01

    Full Text Available The hypoxic tumor environment has been shown to be critical to cancer metastasis through the promotion of angiogenesis, induction of epithelial-mesenchymal transition (EMT, and acquisition of invasive potential. However, the impact of hypoxia on the expression profile of the proteolytic enzymes involved in invasiveness is relatively unknown. Membrane-type 4 matrix metalloproteinase (MT4-MMP is a glycosyl-phosphatidyl inositol-anchored protease that has been shown to be overexpressed in human cancers. However, detailed mechanisms regarding the regulation and function of MT4-MMP expression in tumor cells remain unknown. Here, we demonstrate that hypoxia or overexpression of hypoxia-inducible factor-1α (HIF-1α induced MT4-MMP expression in human cancer cells. Activation of SLUG, a transcriptional factor regulating the EMT process of human cancers, by HIF-1α was critical for the induction of MT4-MMP under hypoxia. SLUG regulated the transcription of MT4-MMP through direct binding to the E-box located in its proximal promoter. Short-interference RNA-mediated knockdown of MT4-MMP attenuated in vitro invasiveness and in vivo pulmonary colonization of tumor cells without affecting cell migratory ability. MT4-MMP promoted invasiveness and pulmonary colonization through modulation of the expression profile of MMPs and angiogenic factors. Finally, coexpression of HIF-1α and MT4-MMP in human head and neck cancer was predictive of a worse clinical outcome. These findings establish a novel signaling pathway for hypoxia-mediated metastasis and elucidate the underlying regulatory mechanism and functional significance of MT4-MMP in cancer metastasis.

  15. Early Expression of Pregnancy-Specific Glycoprotein 22 (PSG22) by Trophoblast Cells Modulates Angiogenesis in Mice1

    Science.gov (United States)

    Blois, Sandra M.; Tirado-González, Irene; Wu, Julie; Barrientos, Gabriela; Johnson, Briana; Warren, James; Freitag, Nancy; Klapp, Burghard F.; Irmak, Ster; Ergun, Suleyman; Dveskler, Gabriela S.

    2012-01-01

    ABSTRACT Mouse and human pregnancy-specific glycoproteins (PSG) are known to exert immunomodulatory functions during pregnancy by inducing maternal leukocytes to secrete anti-inflammatory cytokines that promote a tolerogenic decidual microenvironment. Many such anti-inflammatory mediators also function as proangiogenic factors, which, along with the reported association of murine PSG with the uterine vasculature, suggest that PSG may contribute to the vascular adaptations necessary for successful implantation and placental development. We observed that PSG22 is strongly expressed around the embryonic crypt on Gestation Day 5.5, indicating that trophoblast giant cells are the main source of PSG22 during the early stages of pregnancy. PSG22 treatment up-regulated the secretion of transforming growth factor beta 1 and vascular endothelial growth factor A (VEGFA) in murine macrophages, uterine dendritic cells, and natural killer cells. A possible role of PSGs in uteroplacental angiogenesis is further supported by the finding that incubation of endothelial cells with PSG22 resulted in the formation of tubes in the presence and absence of VEGFA. We determined that PSG22, like human PSG1 and murine PSG17 and PSG23, binds to the heparan sulfate chains in syndecans. Therefore, our findings indicate that despite the independent evolution and expansion of human and rodent PSG, members in both families have conserved functions that include their ability to induce anti-inflammatory cytokines and proangiogenic factors as well as to induce the formation of capillary structures by endothelial cells. In summary, our results indicate that PSG22, the most abundant PSG expressed during mouse early pregnancy, is likely a major contributor to the establishment of a successful pregnancy. PMID:22423048

  16. Interaction between SCO-spondin and low density lipoproteins from embryonic cerebrospinal fluid modulates their roles in early neurogenesis

    Directory of Open Access Journals (Sweden)

    América eVera

    2015-05-01

    Full Text Available During early stages of development, encephalic vesicles are composed by a layer of neuroepithelial cells surrounding a central cavity filled with embryonic cerebrospinal fluid (eCSF. This fluid contains several morphogens that regulate proliferation and differentiation of neuroepithelial cells. One of these neurogenic factors is SCO-spondin, a giant protein secreted to the eCSF from early stages of development. Inhibition of this protein in vivo or in vitro drastically decreases the neurodifferentiation process. Other important neurogenic factors of the eCSF are low density lipoproteins (LDL, the depletion of which generates a 60% decrease in mesencephalic explant neurodifferentiation. The presence of several LDL receptor class A (LDLrA domains (responsible for LDL binding in other proteins in the SCO-spondin sequence suggests a possible interaction between both molecules. This possibility was analyzed using three different experimental approaches: 1 Bioinformatics analyses of the SCO-spondin region, that contains eight LDLrA domains in tandem, and of comparisons with the LDL receptor consensus sequence; 2 Analysis of the physical interactions of both molecules through immunohistochemical colocalization in embryonic chick brains and through the immunoprecipitation of LDL with anti-SCO-spondin antibodies; and 3 Analysis of functional interactions during the neurodifferentiation process when these molecules were added to a culture medium of mesencephalic explants. The results revealed that LDL and SCO-spondin interact to form a complex that diminishes the neurogenic capacities that both molecules have separately. Our work suggests that the embryonic cerebrospinal fluid is an active signaling center with a complex regulation system that allows for correct brain development.

  17. High nuclear level of Vav1 is a positive prognostic factor in early invasive breast tumors: a role in modulating genes related to the efficiency of metastatic process.

    Science.gov (United States)

    Grassilli, Silvia; Brugnoli, Federica; Lattanzio, Rossano; Rossi, Cosmo; Perracchio, Letizia; Mottolese, Marcella; Marchisio, Marco; Palomba, Maria; Nika, Ervin; Natali, Pier Giorgio; Piantelli, Mauro; Capitani, Silvano; Bertagnolo, Valeria

    2014-06-30

    Vav1 is one of the signalling proteins normally restricted to hematopoietic cells that results ectopically expressed in solid tumors, including breast cancer. By immunohistochemical analysis on TMAs containing invasive breast tumor from patients without lymph node involvement, we have found that Vav1 is expressed in almost all investigated cancers and shows a peculiar localization inside the nucleus of tumor cells. High amounts of nuclear Vav1 are positively correlated with low incidence of relapse, regardless phenotype and molecular subtype of breast neoplasia. In particular, Kaplan-Meier plots showed an elevated risk of distant metastasis in patients with low Vav1 expression compared with patients with high Vav1 expression in their tumors. Experiments performed with breast tumor-derived cells indicated that Vav1 negatively modulates their invasiveness in vitro and their metastatic efficiency in vivo, possibly by affecting the expression of genes involved in invasion and/or metastasis of breast tumors. Since the high heterogeneity of breast tumors makes difficult to predict the evolution of early breast neoplasias, the evaluation of nuclear Vav1 levels may help in the characterization and management of early breast cancer patients. In particular, Vav1 may serve as a prognostic biomarker and a target for new therapies aimed to prevent breast cancer progression.

  18. Assessment of Early Diastolic Strain-Velocity Temporal Relationships Using SPAMM-PAV (SPAtial Modulation of Magnetization with Polarity Alternating Velocity encoding)

    Science.gov (United States)

    Zhang, Ziheng; Dione, Donald P.; Brown, Peter B.; Shapiro, Erik M.; Sinusas, Albert J.; Sampath, Smita

    2011-01-01

    A novel MR imaging technique, spatial modulation of magnetization with polarity alternating velocity encoding (SPAMM-PAV), is presented to simultaneously examine the left ventricular early diastolic temporal relationships between myocardial deformation and intra-cavity hemodynamics with a high temporal resolution of 14 ms. This approach is initially evaluated in a dynamic flow and tissue mimicking phantom. A comparison of regional longitudinal strains and intra-cavity pressure differences (integration of computed in-plane pressure gradients within a selected region) in relation to mitral valve inflow velocities is performed in eight normal volunteers. Our results demonstrate that apical regions have higher strain rates (0.145 ± 0.005 %/ms) during the acceleration period of rapid filling compared to mid-ventricular (0.114 ± 0.007 %/ms) and basal regions (0.088 ± 0.009 %/ms), and apical strain curves plateau at peak mitral inflow velocity. This pattern is reversed during the deceleration period, when the strain-rates in the basal regions are the highest (0.027 ± 0.003 %/ms) due to ongoing basal stretching. A positive base-to-apex gradient in peak pressure difference is observed during acceleration, followed by a negative base-to apex gradient during deceleration. These studies shed insight into the regional volumetric and pressure difference changes in the left ventricle during early diastolic filling. PMID:21630348

  19. 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

  20. Hypoxia, HIF-1 Regulation and Cancer Therapy

    NARCIS (Netherlands)

    Groot, A.J.

    2008-01-01

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

  1. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

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

  2. Acridine-intercalator based hypoxia selective cytotoxins

    Science.gov (United States)

    Papadopoulou-Rosenzweig, Maria; Bloomer, William D.; Bloomer, William D.

    1994-01-01

    Hypoxia selective cytotoxins of the general formula ##STR1## wherein n is from 1 to 5, and NO.sub.2 is in at least one of the 2, 4 or 5-positions of the imidazole. Such compounds have utility as radiosensitizers and chemosensitizers.

  3. Acridine-intercalator based hypoxia selective cytotoxins

    Energy Technology Data Exchange (ETDEWEB)

    Papadopoulou-Rosenzweig, M.; Bloomer, W.D.

    1994-03-15

    Hypoxia selective cytotoxins of the general formula STR1 wherein n is from 1 to 5, and NO[sub 2] is in at least one of the 2, 4 or 5-positions of the imidazole are developed. Such compounds have utility as radiosensitizers and chemosensitizers. 9 figs.

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...

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

    Science.gov (United States)

    Xiao, Wuhan

    2015-02-01

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

  7. Hypoxia in the Northern Gulf of Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Dale, Virginia H [ORNL

    2010-01-01

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

  8. The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module

    Directory of Open Access Journals (Sweden)

    Rogers Crystal D

    2011-12-01

    Full Text Available Abstract Background The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a. Results To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone. Conclusions We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.

  9. SU-E-T-338: Dosimetric Study of Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) for Stereotactic Body Radiation Therapy (SBRT) in Early Stage Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ahmad, I; Quinn, K; Seebach, A; Wang, H [OSF Saint Anthony Medical Center, Rockford, IL (United States); Yah, R [University of Illinois College of Medicine at Rockford, Rockford, IL (United States)

    2015-06-15

    Purpose: This study evaluates the dosimetric differences using volumetric modulated arc therapy (VMAT) in patients previously treated with intensity modulated radiation therapy IMRT for stereotactic body radiotherapy (SBRT) in early stage lung cancer. Methods: We evaluated 9 consecutive medically inoperable lung cancer patients at the start of the SBRT program who were treated with IMRT from November 2010 to October 2011. These patients were treated using 6 MV energy. The 9 cases were then re-planned with VMAT performed with arc therapy using 6 MV flattening filter free (FFF) energy with the same organs at risk (OARS) constraints. Data collected for the treatment plans included target coverage, beam on time, dose to OARS and gamma pass rate. Results: Five patients were T1N0 and four patients were T2N0 with all tumors less than 5 cm. The average GTV was 13.02 cm3 (0.83–40.87) and average PTV was 44.65 cm3 (14.06–118.08). The IMRT plans had a mean of 7.2 angles (6–9) and 5.4 minutes (3.6–11.1) per plan. The VMAT plans had a mean of 2.8 arcs (2–3) and 4.0 minutes (2.2–6.0) per plan. VMAT had slightly more target coverage than IMRT with average increase in D95 of 2.68% (1.24–5.73) and D99 of 3.65% (0.88–8.77). VMAT produced lower doses to all OARs. The largest reductions were in maximum doses to the spinal cord with an average reduction of 24.1%, esophagus with an average reduction of 22.1%, and lung with an average reduction in the V20 of 16.3% The mean gamma pass rate was 99.8% (99.2–100) at 3 mm and 3% for VMAT with comparable values for IMRT. Conclusion: These findings suggest that using VMAT for SBRT in early stage lung cancer is superior to IMRT in terms of dose coverage, OAR dose and a lower treatment delivery time with a similar gamma pass rate.

  10. Hypoxia increases the behavioural activity of schooling herring: a response to physiological stress or respiratory distress?

    DEFF Research Database (Denmark)

    Herbert, Neill A.; Steffensen, John F.

    2006-01-01

    a deviation in physiological homeostasis is associated with any change in behavioural activity, we exposed C. harengus in a school to a progressive stepwise decline in water oxygen pressure  and measured fish swimming speed and valid indicators of primary and secondary stress (i.e. blood cortisol, lactate......Atlantic herring, Clupea harengus, increase their swimming speed during low O2 (hypoxia) and it has been hypothesised that the behavioural response is modulated by the degree of "respiratory distress" (i.e. a rise in anaerobic metabolism and severe physiological stress). To test directly whether......, glucose and osmolality). Herring in hypoxia increased their swimming speed by 11-39% but only when  was cortisol also exhibited an increase with  plasma osmolality was subject to a transient rise at 8.5 k...

  11. Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells: role of autophagy and JNK activation.

    Science.gov (United States)

    Notte, A; Ninane, N; Arnould, T; Michiels, C

    2013-05-16

    Cancer cell resistance against chemotherapy is still a heavy burden to improve anticancer treatments. Autophagy activation and the development of hypoxic regions within the tumors are known to promote cancer cell resistance. Therefore, we sought to evaluate the role of autophagy and hypoxia on the taxol-induced apoptosis in MDA-MB-231 breast cancer cells. The results showed that taxol induced apoptosis after 16 h of incubation, and that hypoxia protected MDA-MB-231 cells from taxol-induced apoptosis. In parallel, taxol induced autophagy activation already after 2 h of incubation both under normoxia and hypoxia. Autophagy activation after taxol exposure was shown to be a protective mechanism against taxol-induced cell death both under normoxia and hypoxia. However, at longer incubation time, the autophagic process reached a saturation point under normoxia leading to cell death, whereas under hypoxia, autophagy flow still correctly took place allowing the cells to survive. Autophagy induction is induced after taxol exposure via mechanistic target of rapamycin (mTOR) inhibition, which is more important in cells exposed to hypoxia. Taxol also induced c-Jun N-terminal kinase (JNK) activation and phosphorylation of its substrates B-cell CLL/lymphoma 2 (Bcl2) and BCL2-like 1 (BclXL) under normoxia and hypoxia very early after taxol exposure. Bcl2 and BclXL phosphorylation was decreased more importantly under hypoxia after long incubation time. The role of JNK in autophagy and apoptosis induction was studied using siRNAs. The results showed that JNK activation promotes resistance against taxol-induced apoptosis under normoxia and hypoxia without being involved in induction of autophagy. In conclusion, the resistance against taxol-induced cell death observed under hypoxia can be explained by a more effective autophagic flow activated via the classical mTOR pathway and by a mechanism involving JNK, which could be dependent on Bcl2 and BclXL phosphorylation but independent of

  12. Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells: role of autophagy and JNK activation

    Science.gov (United States)

    Notte, A; Ninane, N; Arnould, T; Michiels, C

    2013-01-01

    Cancer cell resistance against chemotherapy is still a heavy burden to improve anticancer treatments. Autophagy activation and the development of hypoxic regions within the tumors are known to promote cancer cell resistance. Therefore, we sought to evaluate the role of autophagy and hypoxia on the taxol-induced apoptosis in MDA-MB-231 breast cancer cells. The results showed that taxol induced apoptosis after 16 h of incubation, and that hypoxia protected MDA-MB-231 cells from taxol-induced apoptosis. In parallel, taxol induced autophagy activation already after 2 h of incubation both under normoxia and hypoxia. Autophagy activation after taxol exposure was shown to be a protective mechanism against taxol-induced cell death both under normoxia and hypoxia. However, at longer incubation time, the autophagic process reached a saturation point under normoxia leading to cell death, whereas under hypoxia, autophagy flow still correctly took place allowing the cells to survive. Autophagy induction is induced after taxol exposure via mechanistic target of rapamycin (mTOR) inhibition, which is more important in cells exposed to hypoxia. Taxol also induced c-Jun N-terminal kinase (JNK) activation and phosphorylation of its substrates B-cell CLL/lymphoma 2 (Bcl2) and BCL2-like 1 (BclXL) under normoxia and hypoxia very early after taxol exposure. Bcl2 and BclXL phosphorylation was decreased more importantly under hypoxia after long incubation time. The role of JNK in autophagy and apoptosis induction was studied using siRNAs. The results showed that JNK activation promotes resistance against taxol-induced apoptosis under normoxia and hypoxia without being involved in induction of autophagy. In conclusion, the resistance against taxol-induced cell death observed under hypoxia can be explained by a more effective autophagic flow activated via the classical mTOR pathway and by a mechanism involving JNK, which could be dependent on Bcl2 and BclXL phosphorylation but

  13. Effect of hypoxia on cerebrovascular and cognitive function during moderate intensity exercise.

    Science.gov (United States)

    Lefferts, Wesley K; Babcock, Matthew C; Tiss, Matthew J; Ives, Stephen J; White, Corey N; Brutsaert, Tom D; Heffernan, Kevin S

    2016-10-15

    Exercise in hypoxia places added demands on the brain and cerebrovasculature that can impact cognitive function. The purpose of this study was to investigate the effect of acute hypoxia on cerebrovascular hemodynamics, markers of neuro-steroidal modulation and brain-blood barrier (BBB) integrity, and cognition during exercise. Thirty healthy participants (21±4yrs., BMI 24.0±2.6kg∙m(-2); 15 men) were randomized to both a≈2.5h normoxic (FiO2 20.0%) and hypoxic (FiO2 12.5%) condition on two separate days. After 1.25h, participants underwent 10min of exercise-alone (cycling at 55% HRmax) and 15min of exercise+cognitive testing. Prefrontal cortex (PFC) tissue oxygenation and middle cerebral artery (MCA) mean blood velocity (MnV) were measured using near-infrared spectroscopy and transcranial Doppler respectively at rest, during exercise-alone, and during exercise+cognitive testing. Salivary levels of dehydroepiandosterone [DHEA], DHEA-sulfate [DHEAS]) and neuron specific enolase (NSE) were measured pre and post exercise. Cognition was assessed using standard metrics of accuracy and reaction time (RT), and advanced metrics from drift-diffusion modeling across memory recognition, N-Back and Flanker tasks. MCA MnV increased from rest to exercise (pDHEA and NSE increased and decreased post-exercise, respectively, in both normoxia and hypoxia (pmemory recognition (pmemory RT were due to increases in caution (p<0.01). Overall cognitive performance is maintained during exercise in hypoxia concomitant with slower RT in select cognitive tasks and reduced oxygenation in the PFC. These changes were accompanied by slight increases in neuro-steroidal modulation but appear independent of changes in NSE, a biomarker of BBB integrity. Maintained accuracy and select increases in RT during hypoxic exercise may be related behavioral changes in caution. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Differential modulation of motor cortical plasticity and excitability in early and late phases of human motor learning.

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    Rosenkranz, Karin; Kacar, Aleksandra; Rothwell, John C

    2007-10-31

    Different phases of motor skill learning appear to involve different physiological processes, with long-term potentiation (LTP) occurring at existing synapses in early and cortical reorganization involving synaptogenesis in later phases. Here, we test the evolution of skill learning-dependent changes in motor plasticity and excitability in six subjects trained to perform rapid thumb abductions over 5 d. Plasticity was examined using paired-associative stimulation (PAS) of the median nerve and motor cortex to induce LTP-like "PAS given with an interstimulus interval of 25 ms (PAS25)" or long-term depression (LTD)-like "PAS given with an interstimulus interval of 10 ms (PAS10)" plasticity. Excitability was tested by measuring recruitment of motor-evoked-potentials "input-output (IO) curve" and of short-latency intracortical inhibition (SICI curve), and sensorimotor organization (SMO). Task performance improved continuously over 5 d. After practice on day 1, the PAS25 effect reversed from facilitation to inhibition whereas the slope of the IO curve increased and the level of SICI decreased. These effects on IO curve and SICI were still present or even enhanced before the last practice on day 5, and were not changed by it. The effect of proprioceptive input from the trained muscle on SMO was also strengthened before practice on day 5. In contrast, PAS-induced plasticity was not influenced by motor practice on day 5, and had returned to prepractice values. The interference with PAS-induced plasticity suggests that the initial performance improvement relies on increasing the efficacy of existing synaptic connections. However, the long-lasting changes in the IO curve, SICI curve, and SMO suggest that continued practice enhances performance by changing Motor cortical organization. We hypothesize that new synaptic connections might have formed that allow LTP/LTD-susceptibility to be restored without reducing synaptic strength and performance skill.

  15. Rare variants in calcium homeostasis modulator 1 (CALHM1 found in early onset Alzheimer's disease patients alter calcium homeostasis.

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    Fanny Rubio-Moscardo

    Full Text Available Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD. Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+-permeable channel CALHM1. A genetic polymorphism (p. P86L in CALHM1 reduces plasma membrane Ca(2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD, we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H and one (p.A213T in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T behaved as wild-type CALHM1 (CALHM1-WT, a complete abolishment of the Ca(2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H. Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

  16. Increased activity of the antioxidants systems modulate the oxidative stress in saliva of toddlers with early childhood caries.

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    Silva, Priscila Vieira da; Troiano, Jéssica Antonini; Nakamune, Ana Cláudia M S; Pessan, Juliano Pelim; Antoniali, Cristina

    2016-10-01

    This study aimed to evaluate the oxidative stress levels and the enzymatic and non-enzymatic antioxidant systems in saliva of toddlers with severe early childhood caries (S-ECC). Unstimulated saliva samples were collected at the morning from 0 to 3 year-old S-ECC (n=30) or caries-free (CF) children (n=30/group) for evaluation of oxidative stress (OS) and total antioxidant capacity (TAC), which were measured by the ferric reducing antioxidant power (FRAP) assay, as well as to assess the activity of enzymatic (superoxide dismutase, SOD) and non-enzymatic (uric acid, UA) antioxidant systems, respectively. Data were analyzed by Student's t-test (psaliva of S-ECC children (0.083mg/mL) than in the CF group (0.070mg/mL). Oxidative damage was significantly lower in saliva of S-ECC children (0.0019μmol/L/mg protein) than in CF children (0.0039μmol/L/mg protein), while salivary TAC (61.5μmol/L), SOD activity (36.6 UE/mL) and uric acid (7.05mg/mL) were significantly higher in saliva of S-ECC when compared to the CF group (49.1μmol/L, 26.8 UE/mL and 5.02mg/mL, respectively for TAC, SOD and UA). Oxidative stress levels were significantly lower in saliva of S-ECC children, what might be associated with the increased activity of salivary enzymatic (SOD) and non-enzymatic (uric acid) antioxidant systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma. Early results of a phase II study

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    Yu, Wei-Wei [Fudan University, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai (China); Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Department of Radiation Oncology, Shanghai (China); Zhu, Zheng-Fei; Zhao, Kuai-Le; Mao, Jing-Fang; Wu, Kai-Liang; Yang, Huan-Jun; Fan, Min; Zhao, Sen [Fudan University, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai (China); Fu, Xiao-Long [Fudan University Cancer Hospital, Department of Radiation Oncology, Shanghai (China); Fudan University, Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai (China); Welsh, James [The University of Texas MD Anderson Cancer Center, Departments of Radiation Oncology, Houston, Texas (United States)

    2014-11-15

    The safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phase II setting. Between June 2007 and October 2009, 45 patients underwent concurrent chemoradiotherapy (n = 27) or radiotherapy alone (n = 18). Two planning target volumes (PTV) were defined for the SIB: PTV{sub C} and PTV{sub G}, with prescribed doses of 50.4 Gy to the PTV{sub C} (1.8 Gy/fraction) and 63 Gy to the PTV{sub G} (2.25 Gy/fraction), both given in 28 fractions. At a median follow-up interval of 20.3 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 42.2 and 40.7 %, respectively. The median overall survival time was 21 months; locoregional control rates were 83.3 % at 1 year and 67.5 % at 3 years. According to CTCAE (version 3.0) criteria, none of the patients developed grade 4-5 toxicity. The most common grade 2 and 3 radiation-related toxicity was radiation esophagitis, occurring in 64 % of all patients (but only 13 % as grade 3). No patient developed grade > 2 pulmonary complications. SIB-IMRT is a feasible therapeutic approach for esophageal carcinoma patients and provides encouraging locoregional control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies. (orig.) [German] Die Wirksamkeit und Effektivitaet einer intensitaetsmodulierten Radiotherapie mit einem simultan integrierten Boost (SIB-IMRT) fuer Patienten mit Oesophaguskarzinom wurde in einer Single-Institution-Phase-II-Studie bewertet. Zwischen Juni 2007 und Oktober 2009 wurden 45 Patienten mit einer simultanen Radiochemotherapie (n = 27) oder einer alleinigen Strahlentherapie (n = 18) behandelt. Zwei Planungszielvolumen (PTV) wurden fuer die SIB definiert: PTV{sub C} und PTV{sub G}, mit vorgeschriebenen Dosen von 50,4 Gy fuer PTV{sub C} (1,8 Gy/Fraktion) und 63 Gy

  18. Remifentanil protects human keratinocytes against hypoxia-reoxygenation injury through activation of autophagy.

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    Kwon, Jae-Young; Park, Bong-Soo; Kim, Yong-Ho; Kim, Yong-Deok; Kim, Cheul-Hong; Yoon, Ji-Young; Yoon, Ji-Uk

    2015-01-01

    The proliferation, differentiation, and migration of keratinocytes are essential in the early stages of wound healing. Hypoxia-Reoxygenation (H/R) injury to keratinocytes can occur in various stressful environments such as surgery, trauma, and various forms of ulcers. The effects of remifentanil on human keratinocytes under hypoxia-reoxygenation have not been fully studied. Therefore, we investigated the effects of remifentanil on the proliferation, apoptosis, and autophagic activation of human keratinocytes during hypoxic-reoxygenation. Human keratinocytes were cultured under 1% oxygen tension for 24 h. The cells were then treated with various concentrations of remifentanil (0.01, 0.1, 0.5, and 1 ng/mL) for 2 h. Thereafter, the cells were reoxygenated for 12 h at 37°C. We measured cell viability via MTT assay. Using quantitative real-time PCR and western blot analysis, we measured the expression levels of proteins associated with apoptosis and autophagy. Quantification of apoptotic cells was performed using flow cytometer analysis and autophagic vacuoles were observed under a fluorescence microscope. Remifentanil treatment brought about an increase in the proliferation of human keratinocytes damaged by hypoxia-reoxygenation and decreased the apoptotic cell death, enhancing autophagic activity. However, the autophagy pathway inhibitor 3-MA inhibited the protective effect of remifentanil in hypoxia-reoxygenation injury. In conclusion, the current study demonstrated that remifentanil treatment stimulated autophagy and reduced apoptotic cell death in a hypoxia-reoxygenation model of human keratinocytes. Our results provide additional insights into the relationship between apoptosis and autophagy.

  19. Nitric oxide-driven hypoxia initiates synovial angiogenesis, hyperplasia and inflammatory lesions in mice.

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    Fei Bao

    Full Text Available BACKGROUND: Rheumatoid arthritis (RA is an inflammatory articular disease with cartilage and bone damage due to hyperplasic synoviocyte invasion and subsequent matrix protease digestion. Although monoclonal antibodies against tumor necrosis factor alpha (TNFα have been approved for clinical use in patients with RA, desired therapeutic regimens suitable for non-responders are still unavailable because etiological initiators leading to RA remain enigmatic and unidentified. METHODOLOGY/PRINCIPAL FINDINGS: Bacteria-induced arthritis (BIA that simulates collagen-induced arthritis (CIA is developed in mice upon daily live bacterial feeding. The morphological lesions of paw erythema and edema together with the histological alterations of synovial hyperplasia and lymphocytic infiltration emerge as the early-phase manifestations of BIA and CIA. Bacteria- or collagen-mediated global upregulation of pro-inflammatory cytokines is accompanied by the burst of nitric oxide (NO. Elevation of the serum NO level is correlated with decline of the blood oxygen saturation percentage (SpO2, reflecting a hypoxic consequence during development towards arthritis. NO-driven hypoxia is further evident from a positive relationship between NO and lactic acid (LA, an end product from glycolysis. Upregulation of hypoxia inducible factor 1 alpha (HIF-1α and vascular endothelial growth factor (VEGF validates hypoxia-induced angiogenesis in the inflamed synovium of modeling mice. Administration of the NO donor compound sodium nitroprusside (SNP causes articular inflammation by inducing synovial hypoxia. Anti-bacteria by the antibiotic cefotaxime and/or the immunosuppressant rapamycin or artesunate that also inhibits nitric oxide synthase (NOS can abrogate NO production, mitigate hypoxia, and considerably ameliorate or even completely abort synovitis, hence highlighting that NO may serve as an initiator of inflammatory arthritis. CONCLUSIONS/SIGNIFICANCE: Like collagen

  20. Remifentanil protects human keratinocytes against hypoxia-reoxygenation injury through activation of autophagy.

    Directory of Open Access Journals (Sweden)

    Jae-Young Kwon

    Full Text Available The proliferation, differentiation, and migration of keratinocytes are essential in the early stages of wound healing. Hypoxia-Reoxygenation (H/R injury to keratinocytes can occur in various stressful environments such as surgery, trauma, and various forms of ulcers. The effects of remifentanil on human keratinocytes under hypoxia-reoxygenation have not been fully studied. Therefore, we investigated the effects of remifentanil on the proliferation, apoptosis, and autophagic activation of human keratinocytes during hypoxic-reoxygenation. Human keratinocytes were cultured under 1% oxygen tension for 24 h. The cells were then treated with various concentrations of remifentanil (0.01, 0.1, 0.5, and 1 ng/mL for 2 h. Thereafter, the cells were reoxygenated for 12 h at 37°C. We measured cell viability via MTT assay. Using quantitative real-time PCR and western blot analysis, we measured the expression levels of proteins associated with apoptosis and autophagy. Quantification of apoptotic cells was performed using flow cytometer analysis and autophagic vacuoles were observed under a fluorescence microscope. Remifentanil treatment brought about an increase in the proliferation of human keratinocytes damaged by hypoxia-reoxygenation and decreased the apoptotic cell death, enhancing autophagic activity. However, the autophagy pathway inhibitor 3-MA inhibited the protective effect of remifentanil in hypoxia-reoxygenation injury. In conclusion, the current study demonstrated that remifentanil treatment stimulated autophagy and reduced apoptotic cell death in a hypoxia-reoxygenation model of human keratinocytes. Our results provide additional insights into the relationship between apoptosis and autophagy.

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

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

    2010-01-01

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

  2. Hypoxia induces adipogenic differentitation of myoblastic cell lines

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    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.

  3. Behavioural effects of near-term acute fetal hypoxia in a small precocial animal, the spiny mouse (Acomys cahirinus).

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    Ireland, Zoe; Dickinson, Hayley; Fleiss, Bobbi; Hutton, Lisa C; Walker, David W

    2010-01-01

    We have previously developed a model of near-term intra-uterine hypoxia producing significant neonatal mortality (37%) in a small laboratory animal - the spiny mouse - which has precocial offspring at birth. The aim of the present study was to determine if this insult resulted in the appearance of behavioural abnormalities in those offspring which survived the hypoxic delivery. Behavioural tests assessed gait (using footprint patterns), motor coordination and balance on an accelerating rotarod, and spontaneous locomotion and exploration in an open field. We found that the near-term acute hypoxic episode produced a mild neurological deficit in the early postnatal period. In comparison to vaginally delivered controls, hypoxia pups were able to remain on the accelerating rotarod for significantly shorter durations on postnatal days 1-2, and in the open field they travelled significantly shorter distances, jumped less, and spent a greater percentage of time stationary on postnatal days 5 and 15. No changes were observed in gait. Unlike some rodent models of cerebral hypoxia-ischaemia, macroscopic examination of the brain on postnatal day 5 showed no gross cystic lesions, oedema or infarct. Future studies should be directed at identifying hypoxia-induced alterations in the function of specific brain regions, and assessing if maternal administration of neuroprotective agents can prevent against hypoxia-induced neurological deficits and brain damage that occur at birth.

  4. [Inhibitory effect of salidroside on hypoxia-induced apoptosis of corpus cavernosum smooth muscle cells in rats].

    Science.gov (United States)

    Zhao, Jian-Feng; Fu, Hui-Ying; Yang, Fan; Huang, Xiao-Jun; Chen, Gang; Lü, Bo-Dong

    2014-04-01

    To investigate the effect of salidroside on hypoxia-induced apoptosis of corpus cavernosum smooth muscle cells (CCSMCs) in rats. Rat CCSMCs were cultured in vitro by the enzyme digestion method and identified by immunofluorescent staining of anti-alpha-SMA and anti-Desmin. The non-toxic dose of salidroside was determined by MTT assay. Low-oxygen mixed gas (1% O2, 5% CO2, and 94% N2) was piped into a modular incubator chamber to induce hypoxia. The CCSMCs were divided into a normal, a hypoxia, and a 32 microg/mL salidroside intervention group. The apoptosis of the CCSMCs was detected by flow cytometry and the expression of the caspase-3 protein determined by Western blot. The majority of the CCSMCs were positive for alpha-SMA and Desmin at immunofluorescent staining. Salidroside at salidroside significantly reduced hypoxia-induced early apoptosis of CCSMCs ([13.46% +/- 1.87]%, P Salidroside can reduce the expression of cleaved caspase-3 and inhibit hypoxia-induced apoptosis of CCSMCs in rats.

  5. Intensity Modulated Proton and Photon Therapy for Early Prostate Cancer With or Without Transperineal Injection of a Polyethylen Glycol Spacer: A Treatment Planning Comparison Study

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    Weber, Damien C., E-mail: damien.weber@unige.ch [Department of Radiation Oncology, Geneva University Hospital, Geneva (Switzerland); Zilli, Thomas [Department of Radiation Oncology, Geneva University Hospital, Geneva (Switzerland); Vallee, Jean Paul [Department of Diagnostic Radiology, Geneva University Hospital, Geneva (Switzerland); Rouzaud, Michel; Miralbell, Raymond [Department of Radiation Oncology, Geneva University Hospital, Geneva (Switzerland); Cozzi, Luca [Oncology Institute of Southern Switzerland, Medical Physics Unit, Bellinzona (Switzerland)

    2012-11-01

    Purpose: Rectal toxicity is a serious adverse effect in early-stage prostate cancer patients treated with curative radiation therapy (RT). Injecting a spacer between Denonvilliers' fascia increases the distance between the prostate and the anterior rectal wall and may thus decrease the rectal radiation-induced toxicity. We assessed the dosimetric impact of this spacer with advanced delivery RT techniques, including intensity modulated RT (IMRT), volumetric modulated arc therapy (VMAT), and intensity modulated proton beam RT (IMPT). Methods and Materials: Eight prostate cancer patients were simulated for RT with or without spacer. Plans were computed for IMRT, VMAT, and IMPT using the Eclipse treatment planning system using both computed tomography spacer+ and spacer- data sets. Prostate {+-} seminal vesicle planning target volume [PTV] and organs at risk (OARs) dose-volume histograms were calculated. The results were analyzed using dose and volume metrics for comparative planning. Results: Regardless of the radiation technique, spacer injection decreased significantly the rectal dose in the 60- to 70-Gy range. Mean V{sub 70Gy} and V{sub 60Gy} with IMRT, VMAT, and IMPT planning were 5.3 {+-} 3.3%/13.9 {+-} 10.0%, 3.9 {+-} 3.2%/9.7 {+-} 5.7%, and 5.0 {+-} 3.5%/9.5 {+-} 4.7% after spacer injection. Before spacer administration, the corresponding values were 9.8 {+-} 5.4% (P=.012)/24.8 {+-} 7.8% (P=.012), 10.1 {+-} 3.0% (P=.002)/17.9 {+-} 3.9% (P=.003), and 9.7 {+-} 2.6% (P=.003)/14.7% {+-} 2.7% (P=.003). Importantly, spacer injection usually improved the PTV coverage for IMRT. With this technique, mean V{sub 70.2Gy} (P=.07) and V{sub 74.1Gy} (P=0.03) were 100 {+-} 0% to 99.8 {+-} 0.2% and 99.1 {+-} 1.2% to 95.8 {+-} 4.6% with and without Spacer, respectively. As a result of spacer injection, bladder doses were usually higher but not significantly so. Only IMPT managed to decrease the rectal dose after spacer injection for all dose levels, generally with no

  6. The Neuroprotective Potential of Rho-Kinase Inhibition in Promoting Cell Survival and Reducing Reactive Gliosis in Response to Hypoxia in Isolated Bovine Retina

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    Aizhan Alt

    2013-07-01

    Full Text Available Aims: To investigate the outcomes of Rho-kinase inhibition in the electrophysiological ex vivo model of the isolated perfused vertebrate retina under hypoxia. Methods: Bovine retinas were perfused with an oxygen saturated nutrient solution with or without the Rho-kinase inhibitor H-1152P. The retinas were stimulated repeatedly until stable amplitudes were reached and the electroretinogram was recorded at five minute intervals. Hypoxia was induced for 15, 30, and 45 minutes, after which the oxygen saturation was restored. The extent of the cell damage and glial reactivity was determined by Ethidium homodimer-1 staining, immunohistochemistry, and Western blot. Results: Hypoxia caused a time-dependent reduction of the b-wave amplitudes, which could not be prevented by the H-1152P. Although the Rho-kinase inhibitor maintained higher b-wave amplitudes, these effects did not reach statistical significance. Hypoxia also resulted in an increase in cell damage and the activation of the glial cells in the untreated retinas whereas the administration of H-1152P significantly reduced the extent of these events. Conclusion: H-1152P exerted a neuroprotective effect against necrosis on the isolated bovine retina under hypoxia together with a reduction in glial cell reactivity. However, the inhibitor could not prevent the hypoxia induced retinal dysfunction possibly due to the interference with synaptic modulation.

  7. Hypoxia-Induced Upregulation of miR-132 Promotes Schwann Cell Migration After Sciatic Nerve Injury by Targeting PRKAG3.

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    Yao, Chun; Shi, Xiangxiang; Zhang, Zhanhu; Zhou, Songlin; Qian, Tianmei; Wang, Yaxian; Ding, Fei; Gu, Xiaosong; Yu, Bin

    2016-10-01

    Following peripheral nerve injury, hypoxia is formed as a result of defects in blood supply at the injury site. Despite accumulating evidence on the effects of microRNAs (miRNAs) on phenotype modulation of Schwann cells (SCs) after peripheral nerve injury, the impact of hypoxia on SC behaviors through miRNAs during peripheral nerve regeneration has not been estimated. In this study, we confirmed our previous microarray data on the upregulation of miR-132 after sciatic nerve injury in rats and observed that overexpression of miR-132 significantly promoted cell migration of primary cultured SCs. Interestingly, hypoxia-increased expression of miR-132 also enhanced SC migration while inhibition of miR-132 suppressed hypoxia-induced increase in SC migration. miR-132 downregulated PRKAG3 through binding to its 3'-UTR, and PRKAG3 knockdown compromised the reducing effect of miR-132 inhibition on SC migration under normal or hypoxia condition. Moreover, in vivo injection of miR-132 agomir into rats with sciatic nerve transection accelerated SC migration from the proximal to distal stump. Overall, our results suggest that the hypoxia-induced upregulation of miR-132 could promote SC migration and facilitate peripheral nerve regeneration.

  8. Low-frequency stimulation inhibits epileptogenesis by modulating the early network of the limbic system as evaluated in amygdala kindling model.

    Science.gov (United States)

    Wang, Yi; Xu, Zhenghao; Cheng, Hui; Guo, Yi; Xu, Cenglin; Wang, Shuang; Zhang, Jianmin; Ding, Meiping; Chen, Zhong

    2014-09-01

    Low-frequency stimulation (LFS) is emerging as a new option for the treatment of epilepsy. The present study was designed to determine whether there is a crucial period for the treatment of epileptogenesis with LFS. LFS was delivered at different time-points to evaluate its anti-epileptogenic effect on amygdala-kindling rats. (18)F-fluorodeoxyglucose small-animal positron-emission tomography (microPET) and multi-channel EEG recording (MER) were used to investigate the dynamics of brain networks during epileptogenesis and LFS treatment. Interestingly, LFS delivered in the first 7 days significantly retarded the progression of behavioral seizure stages and shortened the afterdischarge duration (ADD), LFS delivered throughout the whole process resulted in similar effects. However, if LFS was delivered at the beginning of seizure stage 2 or 3 (5 ± 0.3 days during kindling acquisition), it had no anti-epileptogenic effect and even prolonged the ADD and enhanced synchronization of the EEGs. MicroPET study revealed a notable hypometabolism in the amygdala, piriform cortex, entorhinal cortex and other regions in the limbic system during the period from seizure stage 0 to stage 2 or 3. The glucose metabolism in those regions was specifically increased by LFS. MER further verified that an early network of afterdischarge spread was formed in those brain regions during kindling acquisition. Thus, we provided direct evidence that modulation of the early network in the limbic system is crucial for the anti-epileptogenic effect of LFS in amygdaloid-kindling rats.

  9. Delivery Parameter Variations and Early Clinical Outcomes of Volumetric Modulated Arc Therapy for 31 Prostate Cancer Patients: An Intercomparison of Three Treatment Planning Systems

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    Shinichi Tsutsumi

    2013-01-01

    Full Text Available We created volumetric modulated arc therapy (VMAT plans for 31 prostate cancer patients using one of three treatment planning systems (TPSs—ERGO++, Monaco, or Pinnacle—and then treated those patients. A dose of 74 Gy was prescribed to the planning target volume (PTV. The rectum, bladder, and femur were chosen as organs at risk (OARs with specified dose-volume constraints. Dose volume histograms (DVHs, the mean dose rate, the beam-on time, and early treatment outcomes were evaluated and compared. The DVHs calculated for the three TPSs were comparable. The mean dose rates and beam-on times for Ergo++, Monaco, and SmartArc were, respectively, 174.3 ± 17.7, 149.7 ± 8.4, and 185.8 ± 15.6 MU/min and 132.7 ± 8.4, 217.6 ± 13.1, and 127.5 ± 27.1 sec. During a follow-up period of 486.2 ± 289.9 days, local recurrence was not observed, but distant metastasis was observed in a single patient. Adverse events of grade 3 to grade 4 were not observed. The mean dose rate for Monaco was significantly lower than that for ERGO++ and SmartArc (P<0.0001, and the beam-on time for Monaco was significantly longer than that for ERGO++ and SmartArc (P<0.0001. Each TPS was successfully used for prostate VMAT planning without significant differences in early clinical outcomes despite significant TPS-specific delivery parameter variations.

  10. Hypoxia inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

    Science.gov (United States)

    Fang, Hsin-Yu; Hughes, Russell; Murdoch, Craig; Coffelt, Seth; Biswas, Subhra K.; Harris, Adrian L.; Johnson, Randall S.; Imityaz, Hongxia Z.; Simon, M. Celeste; Fredlund, Erik; Greten, Florian; Rius, Jordi; Lewis, Claire E.

    2010-01-01

    Ischemia exists in many diseased tissues including arthritic joints, atherosclerotic plaques and malignant tumors. Macrophages accumulate in these sites and upregulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18h. For example, they were seen to upregulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, VEGFA, interleukins 1β and 8, adrenomedullin, CXCR4 and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the NF-κB signalling pathway. We then used both genetic and pharmacological methods to manipulate the levels of HIFs 1α and 2α or NF-κB in primary macrophages in order to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIFs 1 and 2, but not NF-κB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues like malignant tumors. PMID:19454749

  11. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

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

  12. Exogenous HGF Prevents Cardiomyocytes from Apoptosis after Hypoxia via Up-Regulating Cell Autophagy

    Directory of Open Access Journals (Sweden)

    Yunle Wang

    2016-06-01

    Full Text Available Background: Hepatocyte growth factor (HGF is widely known as a protective factor in ischemic myocardium, however HGF sensitive cellular mechanism remained ill-defined. Autophagy at early stage of hypoxia has been demonstrated to play a role in protecting myocardium both in vivo and vitro. We performed this study to investigate the association between the protective effect of HGF and autophagy. Methods: Ventricular myocytes were isolated from neonatal rat heart (NRVMs. We evaluated cardiomyocytes apoptosis by Hoechst staining and flow cytometry. Autophagy was assessed by transmission electron microscope and mRFP-GFP-LC3 adenovirus infection. Mitochondrial membrane potential was estimated by JC-1 staining. Western blotting and ELISA assay were used to quantify protein concentrations. Results: We found that autophagy in NRVMs increased at early stage after hypoxia and HGF release was consistent with the change of autophagy. Exogenous HGF enhanced autophagy and decreased apoptosis, while neutralizing HGF yielded opposite effects. Besides, inhibition of autophagy increased apoptosis of myocytes. Furthermore, exogenous HGF induced Parkin, the marker of mitochondrial autophagy, indicating increased clearance of injured mitochondria. Conclusions: Our results revealed a potential mechanism in which exogenous HGF prevented NRVMs from apoptosis after hypoxia. Upregulation of Parkin through administration of exogenous HGF may be a potential therapeutic strategy ptotecting myocytes during ischemia.

  13. NASA Gulf of Mexico Initiative Hypoxia Research

    Science.gov (United States)

    Armstrong, Curtis D.

    2012-01-01

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

  14. Acute normobaric hypoxia stimulates erythropoietin release.

    Science.gov (United States)

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

    2008-01-01

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

  15. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    Science.gov (United States)

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

    2016-01-01

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

  16. Dose coverage of axillary level I-III areas during whole breast irradiation with simplified intensity modulated radiation therapy in early stage breast cancer patients.

    Science.gov (United States)

    Zhang, Li; Yang, Zhao-Zhi; Chen, Xing-Xing; Tuan, Jeffrey; Ma, Jin-Li; Mei, Xin; Yu, Xiao-Li; Zhou, Zhi-Rui; Shao, Zhi-Min; Liu, Guang-Yu; Guo, Xiao-Mao

    2015-07-20

    This study was designed to evaluate the dose coverage of axillary areas during whole breast irradiation with simplified intensity modulated radiation therapy (s-IMRT) and field-in-field IMRT (for-IMRT) in early stage breast cancer patients. Sixty-one consecutive patients with breast-conserving surgery and sentinel lymph node biopsy were collected. Two plans were created for each patient: the s-IMRT and for-IMRT plan. Dosimetric parameters of axillary areas were compared. The average of mean doses delivered to the axillary level I areas in s-IMRT and for-IMRT plan were 27.7Gy and 29.1Gy (p = 0.011), respectively. The average of V47.5Gy, V45Gy and V40Gy (percent volume receiving≥ 47.5Gy, 45Gy and 40Gy) of the axillary level I in s-IMRT plan was significantly lower than that in for-IMRT plan (p 19.3cm and body width >31.9cm had significantly higher mean dose in axillary level I area (p = 0.002, 0.007, 0.001, respectively). Compared with for-IMRT plan, the s-IMRT plan delivered lower dose to axillary level I area. For centers using s-IMRT technique, caution should be exercised when selecting to omit axillary lymph node dissection for patients with breast conserving surgery and limited positive SLNs.

  17. Volumetric Modulated Arc Therapy of the Pelvic Lymph Nodes to the Aortic Bifurcation in Higher Risk Prostate Cancer: Early Toxicity Outcomes

    Directory of Open Access Journals (Sweden)

    Gina Hesselberg

    2015-01-01

    Full Text Available Background. Treatment of pelvic lymph nodes (PLNs in higher risk prostate carcinoma is controversial. The primary focus of the study was to evaluate the early toxicity profile for this cohort of patients treated with Volumetric Modulated Arc Therapy (VMAT. Methods. Patient, tumour, and treatment characteristics of those who received VMAT from May 2010 to December 2012 were analysed. A simplified contouring process of the PLNs to the aortic bifurcation was developed based on consensus guidelines. Acute and late genitourinary (GU and gastrointestinal (GI toxicities were documented according to the Radiation Therapy Oncology Group (RTOG Version 2 Guidelines. Successive Prostate Specific Antigen (PSA values after treatment were measured on average 3 months apart. Results. 113 patients were treated between May 2010 to December 2012 with a median follow-up of 14 months. No patients experienced acute grade 3 or 4 GU and GI toxicity. Only 1 patient experienced a late grade 3 GU complication. No late grade 4 GU or GI events have yet occurred. Conclusions. This study reviews the first Australian experience of VMAT in the treatment of pelvic lymph nodes in prostate cancer, specifically to the level of the aortic bifurcation. It demonstrates a favorable acute toxicity profile whilst treating large PLN volumes with optimal dose coverage.

  18. Administration of a PTEN inhibitor BPV(pic) attenuates early brain injury via modulating AMPA receptor subunits after subarachnoid hemorrhage in rats.

    Science.gov (United States)

    Chen, Yujie; Luo, Chunxia; Zhao, Mingyue; Li, Qiang; Hu, Rong; Zhang, John H; Liu, Zhi; Feng, Hua

    2015-02-19

    The aim of this study was to investigate whether the phosphatase and tensin homolog deleted on chromosome ten (PTEN) inhibitor dipotassium bisperoxo(pyridine-2-carboxyl) oxovanadate (BPV(pic)) attenuates early brain injury by modulating α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate (AMPA) receptor subunits after subarachnoid hemorrhage (SAH). A standard intravascular perforation model was used to produce the experimental SAH in Sprague-Dawley rats. BPV(pic) treatment (0.2mg/kg) was evaluated for effects on neurological score, brain water content, Evans blue extravasation, hippocampal neuronal death and AMPA receptor subunits alterations after SAH. We found that BPV(pic) is effective in attenuating BBB disruption, lowering edema, reducing hippocampal neural death and improving neurological outcomes. In addition, the AMPA receptor subunit GluR1 protein expression at cytomembrane was downregulated, whereas the expression of GluR2 and GluR3 was upregulated after BPV(pic) treatment. Our results suggest that PTEN inhibited by BPV(pic) plays a neuroprotective role in SAH pathophysiology, possibly by alterations in glutamate AMPA receptor subunits.

  19. The Specific Protein Kinase R (PKR) Inhibitor C16 Protects Neonatal Hypoxia-Ischemia Brain Damages by Inhibiting Neuroinflammation in a Neonatal Rat Model

    Science.gov (United States)

    Xiao, Jinglei; Tan, Yongchang; Li, Yinjiao; Luo, Yan

    2016-01-01

    Background Brain injuries induced by hypoxia-ischemia in neonates contribute to increased mortality and lifelong neurological dysfunction. The specific PKR inhibitor C16 has been previously demonstrated to exert a neuroprotective role in adult brain injuries. However, there is no recent study available concerning its protective role in hypoxia-ischemia-induced immature brain damage. Therefore, we investigated whether C16 protects against neonatal hypoxia-ischemia injuries in a neonatal rat model. Material/Methods Postnatal day 7 (P7) rats were used to establish classical hypoxia-ischemia animal models, and C16 postconditioning with 100 ug/kg was performed immediately after hypoxia. Western blot analysis was performed to quantify the phosphorylation of the PKR at 0 h, 3 h, 6 h, 12 h, 24 h, and phosphorylation of NF-κB 24h after hypoxia exposure. The TTC stain for infarction area and TUNEL stain for apoptotic cells were assayed 24 h after the brain hypoxia. Gene expression of IL-1β, IL-6, and TNF-α was performed at 3 h, 6 h, 12 h, and 24 h. Results The level of PKR autophosphorylation was increased dramatically, especially at 3 h (C16 group vs. HI group, P<0.01). Intraperitoneal C16 administration reduced the infarct volume and apoptosis ratio after this insult (C16 group vs. HI group<0.01), and C16 reduced proinflammatory cytokines mRNA expression, partly through inhibiting NF-κB activation (C16 group vs. HI group<0.05). Conclusions C16 can protect immature rats against hypoxia-ischemia-induced brain damage by modulating neuroinflammation. PMID:28008894

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

    Science.gov (United States)

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

    2016-05-01

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

  1. Dietary supplementation of some antioxidants against hypoxia

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

  2. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Michal Amit Rahat

    2011-09-01

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

  3. Intrauterine hypoxia: clinical consequences and therapeutic perspectives

    Directory of Open Access Journals (Sweden)

    Thompson LP

    2015-09-01

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

  4. Structural integration in hypoxia-inducible factors

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-20

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

  5. Hypoxia in the changing marine environment

    Science.gov (United States)

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

    2013-03-01

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

  6. Sympathoexcitation and arterial hypertension associated with obstructive sleep apnea and cyclic intermittent hypoxia.

    Science.gov (United States)

    Weiss, J Woodrow; Tamisier, Renaud; Liu, Yuzhen

    2015-12-15

    Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction during sleep. These obstructive episodes are characterized by cyclic intermittent hypoxia (CIH), by sleep fragmentation, and by hemodynamic instability, and they result in sustained sympathoexcitation and elevated arterial pressure that persist during waking, after restoration of normoxia. Early studies established that 1) CIH, rather than sleep disruption, accounts for the increase in arterial pressure; 2) the increase in arterial pressure is a consequence of the sympathoactivation; and 3) arterial hypertension after CIH exposure requires an intact peripheral chemoreflex. More recently, however, evidence has accumulated that sympathoactivation and hypertension after CIH are also dependent on altered central sympathoregulation. Furthermore, although many molecular pathways are activated in both the carotid chemoreceptor and in the central nervous system by CIH exposure, two specific neuromodulators-endothelin-1 and angiotensin II-appear to play crucial roles in mediating the sympathetic and hemodynamic response to intermittent hypoxia.

  7. Chronic hypoxia induces the in vivo activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1deltaE9 transgenic mice

    Directory of Open Access Journals (Sweden)

    Lorena eVarela-Nallar

    2014-02-01

    Full Text Available Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin a key component of the canonical Wnt signaling pathway. Here we studied in vivo the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice. As a molecular control of the physiological hypoxic response the hypoxia-inducible transcription factor-1α (HIF-1α was analyzed. Exposure to chronic hypoxia (10% oxygen for 6-72 h stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, BrdU incorporation and double labeling with doublecortin. Chronic hypoxia also induced neurogenesis in double transgenic APPswe-PS1deltaE9 mouse model of Alzheimer’s disease (AD, which shows decreased levels of neurogenesis at the SGZ. Our results show for the first time that in vivo exposure to hypoxia can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorder associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.

  8. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    Science.gov (United States)

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  9. Determinants of maximal oxygen uptake in severe acute hypoxia

    DEFF Research Database (Denmark)

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

    2003-01-01

    To unravel the mechanisms by which maximal oxygen uptake (VO2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, approximately 5,300 m above sea...... level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P ..., as reflected by the higher alveolar-arterial O2 difference in hypoxia (P stroke VOlume (P

  10. Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors

    OpenAIRE

    2014-01-01

    Acidic tissue microenvironment contributes to tumor progression via multiple effects including the activation of angiogenic factors and proteases, reduced cell-cell adhesion, increased migration and invasion, etc. In addition, intratumoral acidosis can influence the uptake of anticancer drugs and modulate the response of tumors to conventional therapy. Acidification of the tumor microenvironment often develops due to hypoxia-triggered oncogenic metabolism, which leads to the extensive product...

  11. Hypoxia and hypercarbia in endophagous insects: Larval position in the plant gas exchange network is key.

    Science.gov (United States)

    Pincebourde, Sylvain; Casas, Jérôme

    2016-01-01

    Gas composition is an important component of any micro-environment. Insects, as the vast majority of living organisms, depend on O2 and CO2 concentrations in the air they breathe. Low O2 (hypoxia), and high CO2 (hypercarbia) levels can have a dramatic effect. For phytophagous insects that live within plant tissues (endophagous lifestyle), gas is exchanged between ambient air and the atmosphere within the insect habitat. The insect larva contributes to the modification of this environment by expiring CO2. Yet, knowledge on the gas exchange network in endophagous insects remains sparse. Our study identified mechanisms that modulate gas composition in the habitat of endophagous insects. Our aim was to show that the mere position of the insect larva within plant tissues could be used as a proxy for estimating risk of occurrence of hypoxia and hypercarbia, despite the widely diverse life history traits of these organisms. We developed a conceptual framework for a gas diffusion network determining gas composition in endophagous insect habitats. We applied this framework to mines, galls and insect tunnels (borers) by integrating the numerous obstacles along O2 and CO2 pathways. The nature and the direction of gas transfers depended on the physical structure of the insect habitat, the photosynthesis activity as well as stomatal behavior in plant tissues. We identified the insect larva position within the gas diffusion network as a predictor of risk exposure to hypoxia and hypercarbia. We ranked endophagous insect habitats in terms of risk of exposure to hypoxia and/or hypercarbia, from the more to the less risky as cambium mines>borer tunnels≫galls>bark mines>mines in aquatic plants>upper and lower surface mines. Furthermore, we showed that the photosynthetically active tissues likely assimilate larval CO2 produced. In addition, temperature of the microhabitat and atmospheric CO2 alter gas composition in the insect habitat. We predict that (i) hypoxia indirectly favors

  12. Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens.

    Directory of Open Access Journals (Sweden)

    Nadine Werth

    Full Text Available BACKGROUND: Hypoxia inducible factor (HIF-1 is the key transcriptional factor involved in the adaptation process of cells and organisms to hypoxia. Recent findings suggest that HIF-1 plays also a crucial role in inflammatory and infectious diseases. METHODOLOGY/PRINCIPAL FINDINGS: Using patient skin biopsies, cell culture and murine infection models, HIF-1 activation was determined by immunohistochemistry, immunoblotting and reporter gene assays and was linked to cellular oxygen consumption. The course of a S. aureus peritonitis was determined upon pharmacological HIF-1 inhibition. Activation of HIF-1 was detectable (i in all ex vivo in biopsies of patients suffering from skin infections, (ii in vitro using cell culture infection models and (iii in vivo using murine intravenous and peritoneal S. aureus infection models. HIF-1 activation by human pathogens was induced by oxygen-dependent mechanisms. Small colony variants (SCVs of S. aureus known to cause chronic infections did not result in cellular hypoxia nor in HIF-1 activation. Pharmaceutical inhibition of HIF-1 activation resulted in increased survival rates of mice suffering from a S. aureus peritonitis. CONCLUSIONS/SIGNIFICANCE: Activation of HIF-1 is a general phenomenon in infections with human pathogenic bacteria, viruses, fungi and protozoa. HIF-1-regulated pathways might be an attractive target to modulate the course of life-threatening infections.

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

    Science.gov (United States)

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

    2015-07-01

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

  14. Crosstalk between nitrite, myoglobin and reactive oxygen species to regulate vasodilation under hypoxia.

    Science.gov (United States)

    Totzeck, Matthias; Hendgen-Cotta, Ulrike B; Kelm, Malte; Rassaf, Tienush

    2014-01-01

    The systemic response to decreasing oxygen levels is hypoxic vasodilation. While this mechanism has been known for more than a century, the underlying cellular events have remained incompletely understood. Nitrite signaling is critically involved in vessel relaxation under hypoxia. This can be attributed to the presence of myoglobin in the vessel wall together with other potential nitrite reductases, which generate nitric oxide, one of the most potent vasodilatory signaling molecules. Questions remain relating to the precise concentration of nitrite and the exact dose-response relations between nitrite and myoglobin under hypoxia. It is furthermore unclear whether regulatory mechanisms exist which balance this interaction. Nitrite tissue levels were similar across all species investigated. We then investigated the exact fractional myoglobin desaturation in an ex vivo approach when gassing with 1% oxygen. Within a short time frame myoglobin desaturated to 58±12%. Given that myoglobin significantly contributes to nitrite reduction under hypoxia, dose-response experiments using physiological to pharmacological nitrite concentrations were conducted. Along all concentrations, abrogation of myoglobin in mice impaired vasodilation. As reactive oxygen species may counteract the vasodilatory response, we used superoxide dismutase and its mimic tempol as well as catalase and ebselen to reduce the levels of reactive oxygen species during hypoxic vasodilation. Incubation of tempol in conjunction with catalase alone and catalase/ebselen increased the vasodilatory response to nitrite. Our study shows that modest hypoxia leads to a significant nitrite-dependent vessel relaxation. This requires the presence of vascular myoglobin for both physiological and pharmacological nitrite levels. Reactive oxygen species, in turn, modulate this vasodilation response.

  15. Neuroepithelial cells and the hypoxia emersion response in the amphibious fish Kryptolebias marmoratus.

    Science.gov (United States)

    Regan, Kelly S; Jonz, Michael G; Wright, Patricia A

    2011-08-01

    Teleost fish have oxygen-sensitive neuroepithelial cells (NECs) in the gills that appear to mediate physiological responses to hypoxia, but little is known about oxygen sensing in amphibious fish. The mangrove rivulus, Kryptolebias marmoratus, is an amphibious fish that respires via the gills and/or the skin. First, we hypothesized that both the skin and gills are sites of oxygen sensing in K. marmoratus. Serotonin-positive NECs were abundant in both gills and skin, as determined by immunohistochemical labelling and fluorescence microscopy. NECs retained synaptic vesicles and were found near nerve fibres labelled with the neuronal marker zn-12. Skin NECs were 42% larger than those of the gill, as estimated by measurement of projection area, and 45% greater in number. Moreover, for both skin and gill NECs, NEC area increased significantly (30-60%) following 7 days of exposure to hypoxia (1.5 mg l(-1) dissolved oxygen). Another population of cells containing vesicular acetylcholine transporter (VAChT) proteins were also observed in the skin and gills. The second hypothesis we tested was that K. marmoratus emerse in order to breathe air cutaneously when challenged with severe aquatic hypoxia, and this response will be modulated by neurochemicals associated chemoreceptor activity. Acute exposure to hypoxia induced fish to emerse at 0.2 mg l(-1). When K. marmoratus were pre-exposed to serotonin or acetylcholine, they emersed at a significantly higher concentration of oxygen than untreated fish. Pre-exposure to receptor antagonists (ketanserin and hexamethonium) predictably resulted in fish emersing at a lower concentration of oxygen. Taken together, these results suggest that oxygen sensing occurs at the branchial and/or cutaneous surfaces in K. marmoratus and that serotonin and acetylcholine mediate, in part, the emersion response.

  16. Effects of systemic hypoxia on human muscular adaptations to resistance exercise training.

    Science.gov (United States)

    Kon, Michihiro; Ohiwa, Nao; Honda, Akiko; Matsubayashi, Takeo; Ikeda, Tatsuaki; Akimoto, Takayuki; Suzuki, Yasuhiro; Hirano, Yuichi; Russell, Aaron P

    2014-06-01

    Hypoxia is an important modulator of endurance exercise-induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise-induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross-sectional area (CSA), one-repetition maximum (1RM), muscular endurance, and makers of mitochondrial biogenesis and angiogenesis, such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), citrate synthase (CS) activity, nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and capillary-to-fiber ratio. Sixteen healthy male subjects were randomly assigned to either a normoxic resistance training group (NRT, n = 7) or a hypoxic (14.4% oxygen) resistance training group (HRT, n = 9) and performed 8 weeks of resistance training. Blood and muscle biopsy samples were obtained before and after training. After training muscle CSA of the femoral region, 1RM for bench-press and leg-press, muscular endurance, and skeletal muscle VEGF protein levels significantly increased in both groups. The increase in muscular endurance was significantly higher in the HRT group. Plasma VEGF concentration and skeletal muscle capillary-to-fiber ratio were significantly higher in the HRT group than the NRT group following training. Our results suggest that, in addition to increases in muscle size and strength, HRT may also lead to increased muscular endurance and the promotion of angiogenesis in skeletal muscle.

  17. Effects of exercise and hypoxia on heart rate variability and acute mountain sickness.

    Science.gov (United States)

    Mairer, K; Wille, M; Grander, W; Burtscher, M

    2013-08-01

    Acute mountain sickness (AMS) is a common condition among non-acclimatized individuals ascending to high altitude. Exercise, a characteristic feature of hiking and mountaineering, has been suggested to exacerbate AMS prevalence and to cause modifications of the autonomic nervous system. A reduction of the heart rate variability (HRV) is a common finding during acute hypoxia, however characteristics of HRV during exercise in subjects suffering from AMS are unknown. Therefore, the aim of the present study was to investigate the effects of acute normobaric hypoxia (FiO2=11.0% ≙ 5 500 m) at rest (PHE) and during exercise (AHE) on the cardiac autonomic function and the development of AMS in 20 healthy, male individuals. HRV recordings were performed during normoxia and after 2, 4, 6 and 8 h in hypoxia during PHE and AHE, respectively. AMS was assessed using the Lake Louise Score. During PHE 50% of participants developed AMS and 70% during AHE (p=0.22). The analysis of HRV data showed a significant reduction of total power (TP), high frequency (HF) and low frequency (LF) components and an increase of the LF:HF ratio during PHE, however without further modification during AHE. Exercise did not increase AMS prevalence or severity, but increased "non-gastrointestinal" symptoms including headache, fatigue and dizziness. HRV indices were not related to the overall incidence of AMS or the development of "non-gastrointestinal" symptoms but we detected significant correlations between gastrointestinal complaints and HRV components. Thus, we suggest that the cardiac autonomic modulation during acute normobaric hypoxia does not play an important role in the development of AMS, but seems to be related to gastrointestinal complaints at high altitude. However, the influence of moderate exercise on HRV and AMS is minor, only "non-GI" symptoms seem to be exacerbated when exercise is applied. © Georg Thieme Verlag KG Stuttgart · New York.

  18. Aromatic Hydrocarbon Receptor Suppresses Prostate Cancer Bone Metastasis Cells-Induced Vasculogenesis of Endothelial Progenitor Cells under Hypoxia

    Directory of Open Access Journals (Sweden)

    Shuai Huang

    2016-07-01

    Full Text Available Background/Aims: Hypoxia leads to the development of neovascularization in solid tumor by regulating VEGF expression. Aromatic hydrocarbon receptor (AHR, a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with hypoxia-inducible factors 1β (HIF-1β and inhibits the secretion of vascular endothelial growth factor (VEGF. The purpose of this study was to explore whether AHR can suppress hypoxia-induced VEGF production in prostate bone metastasis cells and repress neovascularization in endothelial progenitor cells (EPCs, and, if so, through what mechanisms. Methods: PC-3 or LNCaP cells induced angiogenesis was detected by Matrigel-based tube formation assay, mRNA expression levels was measured by qRT-PCR, VEGF secretion level was determined by ELISA assay, respectively. Results: AHR activation inhibits hypoxia-induced adhesiveness and vasculogenesis of EPCs induced by PC-3 or LNCaP cells under hypoxia. Moreover, AHR activation suppressed hypoxia-induced VEGF production in PC-3 and LNCaP cells (48 ± 14% in PC-3, p = 0.000; 41 ± 14% in LNCaP, p = 0.000 by attenuating HIF-1α and HIF-1β level that in turn diminished the angiogenic ability of EPCs in vitro. Furthermore, we found the mRNA level of hypoxia-inducible factors 1α (HIF-1α (1.54 ± 0.13 fold in PC-3, p = 0.002, 1.62 ± 0.12 fold in LNCaP, p = 0.001 and HIF-1β (1.67 ± 0.23 fold in PC-3, p = 0.007; 1.75 ± 0.26 fold in LNCaP, p=0.008 were upregulated in prostate cancer bone metastasis PC-3 and LNCaP cell lines in response to hypoxia, and revealed that the regulation of VEGF by HIF-1α and HIF-1β was possibly mediated by the activation of phosphatidylinositol 3-kinase pathway. Conclusion: By providing a mechanistic insight into the modulation of neovascularization by AHR ligand, we suggest that AHR ligand has a strong potential of being a new therapeutic agent with applications in the field of bone metastatic prostate cancer.

  19. Overexpression of FABP3 inhibits human bone marrow derived mesenchymal stem cell proliferation but enhances their survival in hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Suna, E-mail: wangs3@mail.nih.gov; Zhou, Yifu; Andreyev, Oleg; Hoyt, Robert F.; Singh, Avneesh; Hunt, Timothy; Horvath, Keith A.

    2014-04-15

    Studying the proliferative ability of human bone marrow derived mesenchymal stem cells in hypoxic conditions can help us achieve the effective regeneration of ischemic injured myocardium. Cardiac-type fatty acid binding protein (FABP3) is a specific biomarker of muscle and heart tissue injury. This protein is purported to be involved in early myocardial development, adult myocardial tissue repair and responsible for the modulation of cell growth and proliferation. We have investigated the role of FABP3 in human bone marrow derived mesenchymal stem cells under ischemic conditions. MSCs from 12 donors were cultured either in standard normoxic or modified hypoxic conditions, and the differential expression of FABP3 was tested by quantitative {sup RT}PCR and western blot. We also established stable FABP3 expression in MSCs and searched for variation in cellular proliferation and differentiation bioprocesses affected by hypoxic conditions. We identified: (1) the FABP3 differential expression pattern in the MSCs under hypoxic conditions; (2) over-expression of FABP3 inhibited the growth and proliferation of the MSCs; however, improved their survival in low oxygen environments; (3) the cell growth factors and positive cell cycle regulation genes, such as PCNA, APC, CCNB1, CCNB2 and CDC6 were all down-regulated; while the key negative cell cycle regulation genes TP53, BRCA1, CASP3 and CDKN1A were significantly up-regulated in the cells with FABP3 overexpression. Our data suggested that FABP3 was up-regulated under hypoxia; also negatively regulated the cell metabolic process and the mitotic cell cycle. Overexpression of FABP3 inhibited cell growth and proliferation via negative regulation of the cell cycle and down-regulation of cell growth factors, but enhances cell survival in hypoxic or ischemic conditions. - Highlights: • FABP3 expression pattern was studied in 12 human hypoxic-MSCs. • FABP3 mRNA and proteins are upregulated in the MSCs under hypoxic conditions.

  20. Five-year Results of Whole Breast Intensity Modulated Radiation Therapy for the Treatment of Early Stage Breast Cancer: The Fox Chase Cancer Center Experience

    Energy Technology Data Exchange (ETDEWEB)

    Keller, Lanea M.M., E-mail: Lanea.Keller@fccc.edu [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States); Sopka, Dennis M. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States); Li Tianyu [Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA (United States); Klayton, Tracy; Li Jinsheng; Anderson, Penny R. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States); Bleicher, Richard J.; Sigurdson, Elin R. [Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States); Freedman, Gary M. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States)

    2012-11-15

    Purpose: To report the 5-year outcomes using whole-breast intensity-modulated radiation therapy (IMRT) for the treatment of early-stage-breast cancer at the Fox Chase Cancer Center. Methods and Materials: A total of 946 women with early-stage breast cancer (stage 0, I, or II) were treated with IMRT after surgery with or without systemic therapy from 2003-2010. Whole-breast radiation was delivered via an IMRT technique with a median whole-breast radiation dose of 46 Gy and median tumor bed boost of 14 Gy. Endpoints included local-regional recurrence, cosmesis, and late complications. Results: With a median follow-up of 31 months (range, 1-97 months), there were 12 ipsilateral breast tumor recurrences (IBTR) and one locoregional recurrence. The 5-year actuarial IBTR and locoregional recurrence rates were 2.0% and 2.4%. Physician-reported cosmestic outcomes were available for 645 patients: 63% were considered 'excellent', 33% 'good', and <1.5% 'fair/poor'. For physician-reported cosmesis, boost doses {>=}16 Gy, breast size >900 cc, or boost volumes >34 cc were significantly associated with a 'fair/poor' cosmetic outcome. Fibrosis, edema, erythema, and telangectasia were also associated with 'fair/poor' physician-reported cosmesis; erythema and telangectasia remained significant on multivariate analysis. Patient-reported cosmesis was available for 548 patients, and 33%, 50%, and 17% of patients reported 'excellent', 'good', and 'fair/poor' cosmesis, respectively. The use of a boost and increased boost volume: breast volume ratio were significantly associated with 'fair/poor' outcomes. No parameter for patient-reported cosmesis was significant on multivariate analysis. The chances of experiencing a treatment related effect was significantly associated with a boost dose {>=}16 Gy, receipt of chemotherapy and endocrine therapy, large breast size, and electron boost energy

  1. An investigation of intensity-modulated radiation therapy versus conventional two-dimensional and 3D-conformal radiation therapy for early stage larynx cancer

    Directory of Open Access Journals (Sweden)

    Gomez Daniel

    2010-08-01

    Full Text Available Abstract Introduction Intensity modulated radiation therapy (IMRT has been incorporated at several institutions for early stage laryngeal cancer (T1/T2N0M0, but its utility is controversial. Methods In three representative patients, multiple plans were generated: 1 Conventional 2D planning, with the posterior border placed at either the anterior aspect ("tight" plan or the mid-vertebral body ("loose" plan, 2 3D planning, utilizing both 1.0 and 0.5 cm margins for the planning target volume (PTV, and 3 IMRT planning, utilizing the same margins as the 3D plans. A dosimetric comparison was performed for the target volume, spinal cord, arytenoids, and carotid arteries. The prescription dose was 6300 cGy (225 cGy fractions, and the 3D and IMRT plans were normalized to this dose. Results For PTV margins of 1.0 cm and 0.5 cm, the D95 of the 2D tight/loose plans were 3781/5437 cGy and 5372/5869 cGy, respectively (IMRT/3D plans both 6300 cGy. With a PTV margin of 1.0 cm, the mean carotid artery dose was 2483/5671/5777/4049 cGy in the 2D tight, 2D loose, 3D, and IMRT plans, respectively. When the PTV was reduced to 0.5 cm, the the mean carotid artery dose was 2483/5671/6466/2577 cGy to the above four plans, respectively. The arytenoid doses were similar between the four plans, and spinal cord doses were well below tolerance. Conclusions IMRT provides a more ideal dose distribution compared to 2D treatment and 3D planning in regards to mean carotid dose. We therefore recommend IMRT in select cases when the treating physician is confident with the GTV.

  2. Five-year Local Control in a Phase II Study of Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost for Early Stage Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Freedman, Gary M., E-mail: Gary.Freedman@uphs.upenn.edu [Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Anderson, Penny R. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Bleicher, Richard J. [Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Litwin, Samuel; Li Tianyu [Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Swaby, Ramona F. [Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Ma, Chang-Ming Charlie; Li Jinsheng [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Sigurdson, Elin R. [Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Watkins-Bruner, Deborah [School of Nursing, Emory University, Atlanta, Georgia (United States); Morrow, Monica [Department of Surgical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Goldstein, Lori J. [Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States)

    2012-11-15

    Purpose: Conventional radiation fractionation of 1.8-2 Gy per day for early stage breast cancer requires daily treatment for 6-7 weeks. We report the 5-year results of a phase II study of intensity modulated radiation therapy (IMRT), hypofractionation, and incorporated boost that shortened treatment time to 4 weeks. Methods and Materials: The study design was phase II with a planned accrual of 75 patients. Eligibility included patients aged {>=}18 years, Tis-T2, stage 0-II, and breast conservation. Photon IMRT and an incorporated boost was used, and the whole breast received 2.25 Gy per fraction for a total of 45 Gy, and the tumor bed received 2.8 Gy per fraction for a total of 56 Gy in 20 treatments over 4 weeks. Patients were followed every 6 months for 5 years. Results: Seventy-five patients were treated from December 2003 to November 2005. The median follow-up was 69 months. Median age was 52 years (range, 31-81). Median tumor size was 1.4 cm (range, 0.1-3.5). Eighty percent of tumors were node negative; 93% of patients had negative margins, and 7% of patients had close (>0 and <2 mm) margins; 76% of cancers were invasive ductal type: 15% were ductal carcinoma in situ, 5% were lobular, and 4% were other histology types. Twenty-nine percent of patients 29% had grade 3 carcinoma, and 20% of patients had extensive in situ carcinoma; 11% of patients received chemotherapy, 36% received endocrine therapy, 33% received both, and 20% received neither. There were 3 instances of local recurrence for a 5-year actuarial rate of 2.7%. Conclusions: This 4-week course of hypofractionated radiation with incorporated boost was associated with excellent local control, comparable to historical results of 6-7 weeks of conventional whole-breast fractionation with sequential boost.

  3. Evaluation of the dosimetric impact of applying flattening filter-free beams in intensity-modulated radiotherapy for early-stage upper thoracic carcinoma of oesophagus

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Wuzhe; Lin, Zhixiong; Yang, Zhining; Fang, Weisheng; Lai, Peibo; Lu, Jiayang [Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China); Wu, Vincent WC, E-mail: vincent.wu@polyu.edu.hk [Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, Kowloon (Hong Kong); Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China)

    2015-06-15

    Flattening filter-free (FFF) radiation beams have recently become clinically available on modern linear accelerators in radiation therapy. This study aimed to evaluate the dosimetric impact of using FFF beams in intensity-modulated radiotherapy (IMRT) for early-stage upper thoracic oesophageal cancer. Eleven patients with primary stage upper thoracic oesophageal cancer were recruited. For each patient, two IMRT plans were computed using conventional beams (Con-P) and FFF beams (FFF-P), respectively. Both plans employed a five-beam arrangement and were prescribed with 64 Gy to (planning target volume) PTV1 and 54 Gy to PTV2 in 32 fractions using 6 MV photons. The dose parameters of the target volumes and organs at risks (OARs), and treatment parameters including the monitor units (MU) and treatment time (TT) for Con-P and FFF-P were recorded and compared. The mean D{sub 5} of PTV1 and PTV2 were higher in FFF-P than Con-P by 0.4 Gy and 0.3 Gy, respectively. For the OARs, all the dose parameters did not show significant difference between the two plans except the mean V{sub 5} and V{sub 10} of the lung in which the FFF-P was lower (46.7% vs. 47.3% and 39.1% vs. 39.6%, respectively). FFF-P required 54% more MU but 18.4% less irradiation time when compared to Con-P. The target volume and OARs dose distributions between the two plans were comparable. However, FFF-P was more effective in sparing the lung from low dose and reduced the mean TT compared with Con-P. Long-term clinical studies are suggested to evaluate the radiobiological effects of FFF beams.

  4. Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients

    Directory of Open Access Journals (Sweden)

    Alongi Filippo

    2012-12-01

    Full Text Available Abstract Background SBRT is a safe and efficient strategy to locally control multiple metastatic sites. While research in the physics domain for Flattening Filter Free Beams (FFF beams is increasing, there are few clinical data of FFF beams in clinical practice. Here we reported dosimentric and early clinical data of SBRT and FFF delivery in isolated lymph node oligometastatic patients. Methods Between October 2010 and March 2012, 34 patients were treated with SBRT for oligometastatic lymph node metastasis on a Varian TrueBeamTM treatment machine using Volumetric Modulated Arc Therapy (RapidArc. We retrospectively evaluated a total of 25 patients for isolated lymph node metastases in abdomen and/or pelvis treated with SBRT and FFF (28 treatments. Acute toxicity was recorded. Local control evaluation was scored by means of CT scan and/or PET scan. Results All dosimetric results are in line with what published for the same type of stereotactic abdominal lymph node metastases treatments and fractionation, using RapidArc. All 25 FFF SBRT patients completed the treatment. Acute gastrointestinal toxicity was minimal: one patient showed Grade 1 gastrointestinal toxicity. Three other patients presented Grade 2 toxicity. No Grade 3 or higher was recorded. All toxicities were recovered within one week. The preliminary clinical results at the median follow up of 195 days are: complete response in 12 cases, partial response in 11, stable disease in 5, with an overall response rate of 82%; no local progression was recorded. Conclusions Data of dosimetrical findings and acute toxicity are excellent for patients treated with SBRT with VMAT using FFF beams. Preliminary clinical results showed a high rate of local control in irradiated lesion. Further data and longer follow up are needed to assess late toxicity and definitive clinical outcomes.

  5. Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation

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    Stephan Niebler

    2015-01-01

    Full Text Available The transcription factor AP-2ε (activating enhancer-binding protein epsilon is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2ε expression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2ε mRNA expression comparing initial and late stages of chondrogenic differentiation processes in vitro and in vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker gene angiopoietin-like 4 (Angptl4 strongly correlated with that of AP-2ε suggesting that hypoxia might represent an external regulator of AP-2ε expression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1, the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2′-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1α led to a significantly reduced expression rate of AP-2ε. Additionally, we detected a significant upregulation of the AP-2ε mRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of the AP-2ε gene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2006-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  9. Effect of hypoxia and anoxia on invertebrate behaviour: ecological perspectives from species to community level

    Directory of Open Access Journals (Sweden)

    B. Riedel

    2013-08-01

    Full Text Available Coastal hypoxia and anoxia have become a global key stressor to marine ecosystems, with almost 500 dead zones recorded wordwide. By triggering cascading effects from the individual organism to the community and ecosystem-level, oxygen depletions threat marine biodiversity and can alter ecosystem structure and function. By integrating both physiological function and ecological processes, animal behaviour is ideal for assessing the stress state of benthic macrofauna to low dissolved oxygen. The initial response of organisms can serve as an early-warning signal, while the successive behavioural reactions of key species indicate hypoxia levels and help assess community degradation. Here we document the behavioural responses of a representative spectrum of benthic macrofauna in the natural setting in the Northern Adriatic Sea, Mediterranean. We experimentally induced small-scale anoxia with a benthic chamber in 24 m depth to overcome the difficulties in predicting the onset of hypoxia, which often hinders full documentation in the field. The behavioural reactions were documented with a time-lapse camera. Oxygen depletion elicited significant and repeatable changes in general (visibility, locomotion, body movement and posture, location and species-specific reactions in virtually all organisms (302 individuals from 32 species and 2 species groups. Most atypical (stress behaviours were associated with specific oxygen thresholds: arm-tipping in the ophiuroid Ophiothrix quinquemaculata, for example, with the onset of mild hypoxia (2 L−1, the emergence of polychates on the sediment surface with moderate hypoxia (2 L−1, the emergence of the infaunal sea urchin Schizaster canaliferus on the sediment with severe hypoxia (2 L−1 and heavy body rotations in sea anemones with anoxia. Other species changed their activity patterns, i.e. circadian rhythm in the hermit crab Paguristes eremita or the bioherm-associated crab Pisidia longimana. Intra- and

  10. Hypoxia stimulates invasion and migration of human cervical cancer cell lines HeLa/SiHa through the Rab11 trafficking of integrin αvβ3/FAK/PI3K pathway-mediated Rac1 activation

    Indian Academy of Sciences (India)

    HAO XU; YUAN YUAN; WENQIAN WU; MIN ZHOU; QIAN JIANG; LINJUN NIU; JIAYIN JI; NIANLI LIU; LONGZHEN ZHANG; XIA WANG

    2017-09-01

    Hypoxia plays a key role in tumour cell survival, invasion, and metastasis. An increasing number of studies have attemptedto characterize the tumour response to hypoxia and to identify predictive markers of disease. Here we show that hypoxiaincreases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking.In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervicalcancer cell lines HeLa/SiHa in hypoxia. Activation of Rac1 activity by hypoxia seems to be central to carcinoma invasion.We also found that these effects could be related to the integrin αvβ3. In addition, we studied the molecular pathway for thisprocess. Our results showed that in cervical cancer cell lines HeLa/SiHa, Rac1 activation in hypoxia could stimulateinvasion and migration, and this process was mediated by integrin αvβ3-mediated FAK and PI3K phosphorylation.Furthermore, hypoxia induced a dramatic increase in αvβ3 integrin surface expression, and this increase is dependent onRab11. In conclusion, our study might provide a new mechanism for the effect of hypoxia on stimulating cervicalcarcinoma invasion.

  11. Transient intermittent hypoxia exposure disrupts neonatal bone strength

    Directory of Open Access Journals (Sweden)

    Gyuyoup eKim

    2016-03-01

    Full Text Available A brief intermittent hypoxia (IH, ambient O2 levels alternating between room air and 12% O2 for 1h immediately after birth resulted in pancreatic islet dysfunction associated with zinc deficiency as previously reported. We hypothesized that IH exposure modulates zinc homeostasis in bone as well, which leads to increased bone fragility. To test this hypothesis, we used neonatal rats and human osteoblasts. To examine IH-influences on osteoblasts devoid of neural influences, we quantified amounts of alkaline phosphatase and mineralization in IH-treated human osteoblasts. Bones harvested from IH-treated animals showed significantly reduced hardness and elasticity. The IH group also showed discretely decreased levels of alkaline phosphatase and mineralization amounts. The IH group showed a decreased expression of ZIP8 or Zrt and Irt-like protein 8 (a zinc uptake transporter, Runx2 (or Runt-related transcription factor 2, a master protein in bone formation, Collagen-1 (a major protein comprising the extracellular matrix of the bone, osteocalcin, and zinc content. When zinc was eliminated from the media containing human osteoblasts using a zinc chelate, and added later with zinc sulfate, Runx2, ZIP8 and osteocalcin expression decreased first, and recovered with zinc supplementation. Adenovirus-mediated ZIP8 over-expression in osteoblasts increased mineralization significantly as well. We conclude that IH impairs zinc homeostasis in bones and osteoblasts, and that such disturbances decrease bone strength, which can be recovered by zinc supplementation.

  12. Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  13. Ageing and hypoxia cause protein aggregation in mitochondria.

    Science.gov (United States)

    Kaufman, Daniel M; Wu, Xia; Scott, Barbara A; Itani, Omar A; Van Gilst, Marc R; Bruce, James E; Michael Crowder, C

    2017-10-01

    Aggregation of cytosolic proteins is a pathological finding in disease states, including ageing and neurodegenerative diseases. We have previously reported that hypoxia induces protein misfolding in Caenorhabditis elegans mitochondria, and electron micrographs suggested protein aggregates. Here, we seek to determine whether mitochondrial proteins actually aggregate after hypoxia and other cellular stresses. To enrich for mitochondrial proteins that might aggregate, we performed a proteomics analysis on purified C. elegans mitochondria to identify relatively insoluble proteins under normal conditions (110 proteins identified) or after sublethal hypoxia (65 proteins). A GFP-tagged mitochondrial protein (UCR-11 - a complex III electron transport chain protein) in the normally insoluble set was found to form widespread aggregates in mitochondria after hypoxia. Five other GFP-tagged mitochondrial proteins in the normally insoluble set similarly form hypoxia-induced aggregates. Two GFP-tagged mitochondrial proteins from the soluble set as well as a mitochondrial-targeted GFP did not form aggregates. Ageing also resulted in aggregates. The number of hypoxia-induced aggregates was regulated by the mitochondrial unfolded protein response (UPRmt) master transcriptional regulator ATFS-1, which has been shown to be hypoxia protective. An atfs-1(loss-of-function) mutant and RNAi construct reduced the number of aggregates while an atfs-1(gain-of-function) mutant increased aggregates. Our work demonstrates that mitochondrial protein aggregation occurs with hypoxic injury and ageing in C. elegans. The UPRmt regulates aggregation and may protect from hypoxia by promoting aggregation of misfolded proteins.

  14. Hypoxia-induced retinopathy model in adult zebrafish

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  15. Hypoxia-regulated MicroRNAs in gastroesophageal cancer

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  16. 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...

  17. Lysyl oxidase is essential for hypoxia-induced metastasis

    DEFF Research Database (Denmark)

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

    2006-01-01

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

  18. Brain adaptation to hypoxia and hyperoxia in mice

    Directory of Open Access Journals (Sweden)

    Laura Terraneo

    2017-04-01

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

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  20. Physiological Determinants of Human Acute Hypoxia Tolerance

    Science.gov (United States)

    2013-11-01

    approved in advance by the Civil Aerospace Medical Institute (CAMI) Institutional Review Board for the Protection of Human Subjects, which conforms to the...45.72 ± 10.40 (25.30 – 70.43) Resting VO2 (ml/kg/min) 3.93 ± 0.90 (2.76 – 6.35) DLO2 (ml/mm Hg/min) 40.65 ± 7.72 (25.83 – 59.00) Total Hgb...less SpO2 fell during the 5-min exposure. Max velocity of MCA flow gradually increased after the start of the hypoxia exposure in all subjects and

  1. Cardiorespiratory ontogeny and response to environmental hypoxia of larval spiny lobster, Sagmariasus verreauxi.

    Science.gov (United States)

    Fitzgibbon, Quinn P; Ruff, Nicole; Battaglene, Stephen C

    2015-06-01

    Cardiorespiratory function is vital to an organism's ability to respond to environmental stress and analysis of cardiorespiratory capacity of species or life stages can elucidate vulnerability to climate change. Spiny lobsters have one of the most complex pelagic larval life cycles of any invertebrate and recently there has been an unexplained decline in post-larval recruitment for a number of species. We conducted the first analysis of the larval ontogeny of oxygen consumption, heart rate, maxilla 2 ventilation rate and oxyregulatory capacity of the spiny lobster, Sagmariasus verreauxi, to gain insight into their vulnerability to ocean change and to investigate life stage specific sensitivity to temperature-dependent oxygen limitation. In normoxia, heart and maxilla 2 ventilation rates increased in early larval development before declining, which we hypothesise is related to the transition from myogenic to neurogenic cardiac control. Maxilla 2 ventilation rate was sensitive to hypoxia at all larval stages, while heart rate was only sensitive to hypoxia in the late phyllosoma stages. Oxygen consumption conformed to environmental hypoxia at all larval stages. Spiny lobster larvae have limited respiratory control due to immature gas exchange physiology, compounded by their exceptionally large size. The lack of oxyregulatory ability suggests that all development stages are vulnerable to changes in sea temp