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1
O'Dell, Adam David. "Hypoxia." Bowling Green State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1490629987974442.
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Chacaroun, Samarmar. "Stratégies thérapeutiques par conditionnement hypoxique : modalités pratiques et effets sur la santé cardio-respiratoire et métabolique." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAS020/document.
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L’hypoxie désigne une baisse de la biodisponibilité en oxygène au niveau tissulaire. La combinaison de l’hypoxie intermittente et de l’hypercapnie est identifiée dans le cadre de plusieurs maladies respiratoires comme un élément physiopathologique déterminant. Cependant, des travaux de recherche suggèrent qu’une exposition à l’hypoxie hypo- ou normocapnique à l’éveil peut améliorer la santé cardiovasculaire. La combinaison d’une exposition hypoxique et de l’entraînement à l’effort est utilisée par les athlètes pour améliorer la performance sportive aérobie. Des études pilotes récentes y compris chez le malade chronique indiquent que l’exposition à l’hypoxie modérée au repos ou à l’effort chez le patient est susceptible d’induire des gains significatifs en termes de santé cardiovasculaire, de composition corporelle et de statut métabolique.Nous nous sommes intéressés aux effets cardiorespiratoires et tissulaires de l’exposition hypoxique normobarique chez le sujet sain et chez la personne en surpoids ou obèse présentant un risque ou des anomalies cardio-métaboliques. Nous avons étudié l’efficacité de 2 types de conditionnement au repos consistant en une hypoxie continue ou une hypoxie intermittente et un entraînement à l’effort hypoxique par comparaison à la situation normoxique. Nous avons tout d’abord étudié les effets d’une exposition hypoxique à court terme au repos chez 14 sujets sains. Nous avons ensuite étudié les effets cardiorespiratoires, tissulaires, vasculaires et métaboliques d’un programme de conditionnement hypoxique normobarique à moyen terme au repos chez 35 patients en surpoids ou obèse. Nous avons de plus réalisé chez 24 sujets sains une étude préliminaire afin de vérifier la faisabilité et de caractériser les réponses cardio-respiratoires et l’oxygénation tissulaire au cours d’un exercice aigu à charge constante d’intensité modérée ou intermittent intense en hypoxie comparé à une condition placébo normoxique. La dernière étude a consisté à étudier les conséquences cardiorespiratoires, tissulaires, vasculaires et métaboliques d’un programme d’entraînement à l’effort en hypoxie par rapport au même programme en normoxie chez 23 patients en surpoids ou obèses.L’étude réalisée chez le sujet sain met en évidence l’intérêt à court terme d’un conditionnement hypoxique intermittent au repos sur des variables associées aux risques cardiovasculaires (diminution de la pression artérielle systolique en normoxie et augmentation de la variabilité sinusale) et une modulation de l’hypoxie tissulaire. Nous avons montré chez le sujet sain que l’hypoxie combiné à l’exercice aigu provoque une diminution de l’oxygénation musculaire similaire mais une diminution de l’oxygénation du cortex préfrontal plus importante par comparaison à un effort normoxique à même intensité relative. Ensuite, chez le sujet en surpoids ou obèse, nous avons montré que le conditionnement hypoxique passif chronique induit une diminution de la pression artérielle diastolique de repos en normoxie, une augmentation de la réponse ventilatoire hypoxique et une diminution de la variabilité cardiaque (après conditionnement par hypoxie intermittente seulement) et que le conditionnement hypoxique actif chronique améliore l’aptitude maximale aérobie par rapport à une situation placébo normoxique.Les résultats obtenus montrent la faisabilité de plusieurs conditionnements hypoxiques prometteurs au plan vasculaire y compris chez le sujet en surpoids ou obèse limité à l’exercice musculaire. Le conditionnement hypoxique actif montre également des bénéfices accrus sur l’aptitude aérobie. Ces protocoles de conditionnement doivent être affinés en vue d’optimiser leur efficacité en termes de perte de poids et d’amélioration du risque cardio-vasculaire et métabolique dans des populations présentant une obésité associée à une morbidité cardio-métabolique. Ils représentent également une piste thérapeutique innovante dans d’autres pathologies chroniques<br>Hypoxia refers to a decrease in the oxygen bioavailability at the tissue level. The combination of intermittent hypoxia and hypercapnia is identified in several respiratory diseases as a critical pathophysiological element. However, research suggests that exposure to hypo- or normocapnic hypoxia can improve cardiovascular health. The combination of hypoxic exposure and exercise training has been used by athletes to improve aerobic exercise performance. Recent pilot studies in patients with chronic diseases indicate that exposure to moderate hypoxia at rest or during exercise is likely to induce significant gains in cardiovascular health, body composition and metabolic status.We investigated the effects of normobaric hypoxic exposure on cardiorespiratory and tissue function in healthy subjects, overweight or obese subjects at risk or with cardio-metabolic abnormalities. We assessed the efficacy of 2 types of passive hypoxic conditioning consisting in sustained hypoxia or intermittent hypoxia and hypoxic exercise training in comparison with normoxic condition. First, we assessed the effects of short-term hypoxic exposure at rest in 14 healthy subjects. Then, we evaluated the cardiovascular and metabolic effects of a 8-week normobaric hypoxic conditioning program at rest (intermittent or sustained hypoxia) in 35 overweight or obese patients, compared to placebo normoxic exposure. Next, we conducted a preliminary study in 24 healthy subjects to assess the acute responses to submaximal constant-load and high intensity interval cycling exercise performed in normoxia and in hypoxia. The last study aimed to compare the effect of an 8-week exercise training program performed either in normoxia or hypoxia on maximal aerobic capacity in overweight or obese subjects.In the healthy subject, we emphasized the rapid benefits of intermittent hypoxic conditioning on cardiovascular function (lower baseline systolic blood pressure and increased heart rate variability) and the modulation of tissue deoxygenation in response to hypoxia. We have also shown in healthy subjects that acute exercise (combined with hypoxia causes a similar decrease in muscle oxygenation but a greater prefrontal cortex deoxygenation compared to normoxic condition. Then, in the overweight or obese subject, we have shown that chronic passive hypoxic conditioning induces a decrease in diastolic blood pressure at rest in normoxia, an increase in the hypoxic ventilatory response and a decrease in heart rate variability after intermittent hypoxic conditioning only. In addition, chronic active (exercise training) hypoxic conditioning improves the maximal aerobic capacity compared to placebo normoxic training.Our results show the feasibility of several hypoxic conditioning strategies and their interesting effects on the vascular function in overweight/obese subjects presenting exercise limitations impeding exercise reconditioning. In addition, active hypoxic conditioning showed a greater effect on physical fitness than normoxic exercise training. These hypoxic conditioning strategies must be further optimized to improve their efficacy regarding weight loss and cardiometabolic morbidity in obese. They also represent promising therapeutic opportunities for other chronic diseases
3
Liang, Dinghua. "Progress towards hypoxia-activated SN-38: the potential to target hypoxic tumors." Bentham Science, 2015. http://hdl.handle.net/1993/31591.
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Solid tumors are commonly subject to hypoxia. Hypoxic cancer cells have undesirable properties such as a high tendency to metastasize and resistance to chemotherapy and radiotherapy. Hypoxia-inducible factors (HIFs) respond to the changes in oxygen levels, orchestrating the transcription of many proteins that are vital for the survival of hypoxic cancer cells. With their parent drug SN-38 as an inhibitor of both topoisomerase 1 and HIF-1, hypoxia-activated SN-38s may have a dual inhibitory effect on hypoxic tumor cells due to hypoxia-targeting and HIF-1 inhibition.
To develop hypoxia-activated prodrugs of SN-38; 2-, 3-, and 4-nitrobenzyl SN-38s have been synthesized with good yields (78%, 67% and 68%, respectively). Topoisomerase 1 inhibitory assay on 2- and 4-nitrobenzyl SN-38s and cell viability assay on 2-, 3- and 4-nitrobenzyl SN-38s have been performed. All three derivatives showed less toxicity on K562 cells, which meets the principle of prodrug design. Cyclic voltammetry results suggest that the reduction potentials of these three derivatives may be not high enough for these compounds to be activated. The manner of reduction of three nitrobenzyl SN-38s is quasi-reversible under the testing condition, not against the proposed mechanism of activation. Two new derivatives of SN-38 have been designed to elevate reduction potential and further reduce toxicity. They are to be synthesized and tested for future work.<br>October 2016
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Peters, Caren Lorraine. "Hypoxia in inflammation." Thesis, University of Bath, 2003. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426151.
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Lau, Yue-huen Thomas. "Nuclear transcription factors and hypoxia-inducible genes in chronic liver hypoxia." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31939302.
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Lau, Yue-huen Thomas, and 劉汝這. "Nuclear transcription factors and hypoxia-inducible genes in chronic liver hypoxia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31939302.
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Fantacci, M. "In vivo distribution of Hypoxia-Inducible Factor-1α and DNA fragmentation in hypoxic tumoral and non-tumoral cells: correlation between chronic hypoxia and apoptosis". Doctoral thesis, Università degli Studi di Milano, 2004. http://hdl.handle.net/2434/154279.
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Querido, Jordan S. "Intermittent hypoxia : cardiorespiratory and cerebrovascular consequences to acute hypoxia and submaximal exercise." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/32125.
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Intermittent hypoxia (IH) is broadly defined as repeatedly breathing decreased amounts
of oxygen (hypoxia) interspersed with periods of room air breathing (normoxia). In animal, human diseased, and healthy human models, research has shown IH to negatively affect cerebrovascular vessel dilation. We have previously shown poikilocapnic (uncontrolled carbon dioxide (CO₂)) IH to blunt the vasodilatory response of a cerebral vessel during acute hypoxia.
The purpose of this study was to measure the ventilatory, cardiovascular and cerebrovascular responses to: I) acute hypoxia and; II) to submaximal exercise following an isocapnic (controlled CO₂) IH protocol. Healthy males (n = 9) with normal pulmonary function underwent 10 consecutive days of isocapnic IH (oxyhaemoglobin saturation (SaO₂) = 80%, 1 hr/day). Ventilatory, cardiovascular, and cerebrovascular (transcranial Doppler) responses to acute isocapnic hypoxia (SaO₂ = 80%, 5 minutes) were measured before (PRE-IH) and after (POST-IH) IH. Also, ventilatory, cardiovascular, and cerebrovascular parameters were measured during a submaximal cycle exercise test (50, 100, 150 watts) PRE-IH and POST-IH. To further investigate cerebrovascular regulation during exercise, 5% CO₂ was added for two minutes of each exercise stage. Over the 10 days of IH, there was a significant increase in minute ventilation (VE) during the IH bouts (p<0.05). IH did not significantly alter the ventilatory, cardiovascular,
and cerebrovascular responses to acute hypoxia. However, there was a significant association (r = 0.86, p<0.05) between the change in the mean arterial blood pressure (MAP) and mean middle cerebral arterial blood flow velocity (MCAVm) responses to acute hypoxia. Exercise caused significant increases in VE , MCAVm, and MAP (p<0.05), but there were no differences in measured variables between PRE-IH and POST-IH exercise trials (p>0.05). Similarly, hypercapnia caused significant increases in VE and MCAVm (p<0.05), although the magnitude of the response did not change following IH. Our results suggest that the effect of IH on ventilatory, cardiovascular, and cerebrovascular regulation during acute hypoxia is individualistic, and changes in the MAP response may strongly influence the changes in cerebral blood flow (CBF). Also, our results suggest that IH does not alter ventilatory, cardiovascular, or cerebrovascular regulation during submaximal exercise or responsiveness to hypercapnia.<br>Education, Faculty of<br>Kinesiology, School of<br>Graduate
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Smith, Quintina Denine. "From here to hypoxia." College Park, Md. : University of Maryland, 2006. http://hdl.handle.net/1903/3614.
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Thesis (M.F.A.) -- University of Maryland, College Park, 2006.<br>Thesis research directed by: Dept. of Art. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Holland, Jason P. "Hypoxia-Selective Copper Radiopharmaceuticals." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491536.
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This thesis presents detailed experimental and computational investigations into the chemistry of copper(II) and zinc(II) bis(thiosemicarbazonato) complexes as potential' radiopharmaceutical agents for imaging and therapy. Chapter 1 provides an introduction to the field of molecular imaging in medicine with particular emphasis on the role of positron emission tomography in oncology. Key aspects of tumour physiology are discussed, and the effects of tumour hypoxia on radiotherapy and chemotherapy are considered. A range of hypoxia-selective radiopharmaceuticals are also introduced including a review of the chemistry and biochemistry of copper(II) complexes of bis(thiosemicarbazonato) ligands. Finally, the aims of this thesis are described. Chapter 2 is divided into two sections. The first section provides a general introduction to computational chemistry and density functional theory. The second section describes computational studies on a range of copper(II) bis(thiosemicarbazonato) complexes with the specific aim of understanding the molecular origins of hypoxia-selectivity and facilitating the design of new complexes with greater hypoxia-selectivity. Chapter 3 reports detailed electrochemical, spectroscopic and computational studies aimed at elucidating the mechanism of hypoxia-selectivity of copper(II) bis(thiosemicarbazonato) complexes. Spectroelectrochemistry experiments have been used to characterise several new species. The delicate equilibria between reduction, reoxidation, protonation and ligand dissociation are also considered and a new mechanistic scheme is proposed. Chapter 4 describes the design and optimisation of a new synthetic route which facilitates rapid functionalisation of the copper(II) bis(thiosemicarbazonato) ligands with biologically active molecules. The methodology has been used to synthesise zinc(II) and copper(II) bis(thiosemicarbazonato) complexes functionalised with a diverse range of saccharides. Transmetallation from the zinc(II) analogues using copper(II) salts is described as a fast and efficient route for radiolabelling and copper64 radiolabelled complexes have been prepared and characterised by a range of in vitro and in vivo experiments. Chapter 5 describes the results obtained for several projects designed at increasing the scope of copper-based radiopharmaceuticals. Preliminary synthetic studies towards the development of complexes for imaging Parkinsonian-type diseases and strategies for dual radiolabelling are presented. Chapter 6 gives general conclusions and future prospects for the development of copper-based radiopharmaceuticals. Chapter 7 reports all experimental details.
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Mahamed, Safraaz. "Chemoreflex adaptations to hypoxia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0019/MQ54186.pdf.
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Querido, Jordan Scott. "Hypoxia and autonomic control." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42530.
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Humans have a remarkable ability to cope with and survive exposure to hypoxia. Some have suggested a benefit in certain physiological systems in response to such exposure. However, the physiological response to hypoxia is multifaceted and includes an orchestrated response from many autonomic mechanisms. Thus, the purpose of this thesis was to more fully understand the human autonomic response to hypoxia as an integrated unit. Furthermore, pathological models of hypoxia provide evidence that suggests hypoxia can result in an autonomic response that outlasts the hypoxic stimulus. However, the persistent effect of hypoxia is only evident in certain reflexes, although comorbidities that accompany a pathological model complicate interpretation. Therefore, employing a healthy human model with continued measurement of physiological measures in the post-hypoxia period provides a more complete understanding of the integrated human physiological response to hypoxia. This Doctoral thesis is comprised of four separate investigations, each focusing on autonomic control both during and following an acute hypoxic exposure. In the first study (Chapter 2), the microneurography technique was used to demonstrate that the chemoreflex plays an important role in persistent sympathoexcitation following acute isocapnic hypoxia. With the use of the spontaneous baroreflex analysis technique, the follow-up study (Chapter 3) implicated a resetting of the arterial baroreflex that works to permit the persistent sympathoexcitation. The focus of the third study (Chapter 4) was on cerebrovascular control during fluctuations in blood pressure via bolus injections of vasoactive drugs. There was an improvement in cerebral autoregulation to increases in blood pressure following acute isocapnic hypoxia. The final study (Chapter 5) considered the role of carbon dioxide on hypoxic cerebral autoregulation, and found an impairment in isocapnic hypoxia but no effect in poikilocapnic hypoxia. The findings from this series of studies demonstrate the acute and persistent effects of short-term hypoxia, and the integrated nature in which autonomic mechanisms orchestrate the human physiological response to hypoxia.
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Nagyova, Beatrix Valeria. "Respiratory effects of hypoxia." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320659.
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Dearling, Jason L. J. "Hypoxia targeting copper complexes." Thesis, University of Kent, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297352.
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Alotaibi, Mohammed. "An investigation into the effect of hypoxia in the uterus : does hypoxic preconditioning occur?" Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/10833/.
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During labour, the uterus experiences transient and repeated hypoxic episodes as contractions occlude uterine blood vessels. Despite this, uterine contractions are maintained, their strength gradually increases and labour progresses. The effect of repeated episodes of transient hypoxia on uterine contractility has not been previously investigated and in my study I investigate the hypothesis that multiple transient hypoxic episodes can increase the contractile activity in a pregnant rat uterus near term. Uterine strips were dissected and mounted in organ baths, bubbled with Hepes-buffered, oxygenated physiological saline solution for isometric force recording. The effects of repeated episodes of transient hypoxia (2, 5 or 10min) were studied by replacing the O2 for N2. Hypoxia abolished or significantly reduced the force of uterine contractions in a term-pregnant rat. Upon re-oxygenation, contractile activity was gradually and significantly increased after repeated episodes of transient hypoxia (i.e. similar to “hypoxic preconditioning”), an effect that was most pronounced after 2mins hypoxia. The increased strength of uterine contractions during re-oxygenation periods required the PO2 to be below 10% in the tissue bath during hypoxia. The increase in contractile activity during re-oxygenation was not transient; I found it could be maintained for 11 hrs. During oxytocin stimulation, the response was larger than during spontaneous activity. Moreover, to determine if the response was confined to term-pregnant rats, I examined the effect on rat uteri from different gestations (non-pregnant, 18-day pregnant and labouring). The rebound increase in uterine contractility was not seen in non-pregnant and day 18 pregnant rats with repeated hypoxic episodes, but was present in the labouring rat uterus. Interestingly, data from human uterine biopsies showed the significant rebound increase in contractile activity after the first hypoxic episode in all labouring samples and in one non-labouring sample that was very close to term. These data suggest that hypoxic preconditioning is gestational dependent in both rats and human uteri. To investigate if changes in intracellular calcium were involved in the rebound increase in force, indo-1 loaded myometrial strips from term-pregnant rats were studied. My data showed that initial hypoxia increases the basal [Ca2+]i , but with repeated hypoxia the overall [Ca2+]i decreased gradually suggesting that the increase in contractility was not due to increased [Ca2+]i . In addition, no increase in Ca2+ transients was apparent. Together this may suggest increased sensitivity of contractile machinery to calcium. I found that other mechanisms are likely to be responsible for the increase in contractile activity during hypoxic preconditioning. Repeated episodes of external acidosis were found to partly increase the uterine activity. Hypoxia and no flow resulted in an even larger rebound contractile activity than hypoxia alone. I found, also, that blocking adenosine receptors, particularly A1, abolished the protective effect induced by hypoxic episodes. Repeated episodes of ATP agonist was also found to increase uterine activity in the term-pregnant uterus and blocking P2X7 receptors completely abolished ATP-increased uterine activity. I also found that blocking prostaglandin biosynthesis can block the beneficial effects induced by transient hypoxic episodes in a term-pregnant uterus. Together, these mechanisms which lead to adaptive responses during repeated episodes of transient hypoxia are brought about by multiple changes in the external and internal environment during hypoxic episodes and any defect in any of these mechanisms will prevent the adaptive response to the transient hypoxic episodes. This in turn may have consequences for the progress of human labour.
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Lau, Chi-keung, та 劉智強. "Blockade of hypoxia inducible factor-1α sensitizes hepatocellular carcinoma to hypoxia and chemotherapy". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B39634243.
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Laitala, A. (Anu). "Hypoxia-inducible factor prolyl 4-hydroxylases regulating erythropoiesis, and hypoxia-inducible lysyl oxidase regulating skeletal muscle development during embryogenesis." Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526206943.
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Abstract Erythropoiesis is the process of red blood cell production. The main regulator is the erythropoietin (EPO) hormone, which is strongly upregulated in low oxygen concentration (hypoxia) in cells via the hypoxia-inducible transcription factor HIF. The stability of HIF is regulated in an oxygen-dependent manner by three HIF prolyl 4-hydroxylases, all of which are known to participate in the regulation of erythropoiesis. A role in erythropoiesis of a fourth prolyl 4-hydroxylase, P4H-TM, which possesses a transmembrane domain, is not known, but it is able to hydroxylate HIF at least in vitro and in cellulo. The role of P4H-TM in erythropoiesis was studied by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm null, Hif-p4h-3 null, and Hif-p4h-2 hypomorph mouse lines. The current study suggests that P4H-TM is involved in the regulation of EPO production, hepcidin expression and erythropoiesis. P4H-TM can thus be a new target for inhibition when designing novel pharmacological treatment strategies for anemia. LOX is required for crosslink formation between lysine residues in fibrillar collagens and elastin. These crosslinks enhance the tensile strength of collagen fibers and provide elasticity to elastic fibers and thus generate important structural support for tissues. LOX is required for normal embryonic development of the cardiovascular and pulmonary systems, and its depletion leads to a generalized elastinopathy and collagenolysis leading to perinatal death of Lox null mice. The development of muscles is a delicate process, which requires coordinated signaling and a homeostatic balance between the muscle and muscle connective tissue. Based on the drastic defects that were found in the present study in the skeletal muscle of Lox null mice, lack of LOX clearly disturbs this balance and increases transforming growth factor β (TGF-β) signaling, which leads to defects in the skeletal muscles. The impaired balance can cause muscle disorders, such as Duchenne Muscular Dystrophy (DMD). Despite the clinical significance, very little is known about the mechanisms controlling this homeostatic balance. The discovery of LOX as a regulating factor during skeletal muscle development will help to clarify the role of extracellular matrix (ECM) in muscle development and in muscle related congenital diseases<br>Tiivistelmä Erytropoieesi on fysiologinen prosessi, jossa tuotetaan veren punasoluja ja jonka pääsäätelijänä toimii erytropoietiini (EPO) hormoni. EPO:n geeni ilmentyy voimakkaasti alhaisessa happipitoisuudessa (hypoksia) hypoksia-indusoituvan transkriptiotekijän (HIF) toimesta. HIF-tekijän stabiilisuutta säätelee kolme HIF-prolyyli-4-hydroksylaasientsyymiä (HIF-P4H) hapesta riippuvaisesti, ja niiden tiedetään siten osallistuvan myös erytropoieesin säätelyyn, HIF-P4H-2:n toimiessa pääsäätelijänä. Neljännen transmembraanisen prolyyli-4-hydroksylaasin (P4H-TM) roolia erytropoieesissa ei vielä tiedetä, mutta sen tiedetään säätelevän HIF-tekijää. Työssä käytettiin Hif-p4h-2, Hif-p4h-3 ja P4h-tm muuntogeenisiä hiirilinjoja, joiden entsymaattinen aktiivisuus on alentunut tai poistettu. P4H-TM:n osallisuutta erytropoieesin säätelyyn tutkittiin antamalla hiirilinjoille HIF-P4H-entsyymejä inhiboivaa lääkettä. Tutkimuksen tulokset osoittavat ensimmäistä kertaa P4H-TM:n säätelevän EPO-geenin ilmentymistä ja siten erytropoieesia. Ennestään tiedettyjen HIF-P4H entsyymien inhiboinnin lisäksi P4H-TM:n inhibointia voidaan pitää uutena kohteena uusien farmakologisten hoitokeinojen kehityksessä. Lysyylioksidaasi (LOX) katalysoi säikeisten kollageenien välisten sekä elastisten säikeiden välisten poikkisidosten muodostumista. Pokkisidokset antavat vetolujuutta kollageeneille ja joustavuutta elastisille säikeille ja ovat siten tärkeitä kudoksen rakenteelle. LOX:ia tarvitaan sikiön kehityksen aikana mm. hengitys-, sydän- ja verisuonielimistöjen kehityksessä. LOX:in puutos hiirillä aiheuttaa viallisia elastisia- ja kollageenisäikeitä, johtaen poikasten kuolemaan synnytyksen yhteydessä. Lihasten kehitys on tarkoin säädelty prosessi, jossa lihas ja lihaksen sidekudos säätelevät toisiansa. LOX:n suhteen poistogeenisissä Lox-/- sikiöissä löydettiin selviä ongelmia luurankolihasten kehityksessä. LOX:n puutoksen osoitettiin lisäävän transformoivan kasvutekijä beetan (TGF-β) määrää, joka estää luustolihaksia kehittymästä normaalisti. LOX kykenee sitoutumaan TGF-β:aan ja inhiboimaan sen aktiivisuutta ja LOX:n puuttuessa inhibointia ei tapahdu. Tutkimus osoittaa LOX:n olevan keskeinen tekijä lihaksen kehityksessä ja siten auttaa ymmärtämään sidekudoksen merkitystä luurankolihasten kehityksessä ja siihen liittyvissä sairauksissa
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Sumner, Stephanie Gillian. "Novel use of oxygen-regulated bacterial transcription factors to target gene expression to solid tumours." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366112.
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Dospinescu, Ciprian. "Cellular mechanisms of acute hypoxic pulmonary vasoconstriction in intrapulmonary veins." Thesis, Robert Gordon University, 2009. http://hdl.handle.net/10059/380.
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In the pulmonary circulation, alveolar hypoxia contributes to blood flow regulation. Hypoxic pulmonary vasoconstriction (HPV) involves both pulmonary arteries and veins, but little is known of the contractile mechanisms specific to the veins. The aim of these studies was to examine the hypoxic response in small porcine intrapulmonary veins in relation to the arterial response, and investigate the effects of hypoxia on ion conductances in single myocytes from intrapulmonary veins. In wire myography experiments, intrapulmonary veins contracted more than sizematched arteries in response to hypoxia and agonists KCl and PGF2α. Venous contractions were inhibited by removal of extracellular Ca2+ or in the presence of Clchannel blocker NFA, effects not seen in the arteries. To examine the mechanisms of venous contraction at cellular level, single pulmonary vein smooth muscle cells (PVSMC) were freshly isolated and characterised morphologically and electrophysiologically for the first time. In patch-clamp studies, hypoxia reversibly inhibited a whole-cell outward current in the presence of BKCa channel antagonist Penitrem A. By subtracting currents recorded in normoxia and hypoxia, a novel hypoxia-sensitive K+ current (IK(H)) was revealed in PVSMC. IK(H) was a rapidly activating, partially inactivating current and was sensitive to KV channel blocker 4-AP. The biophysical properties of IK(H) revealed the voltage window of current availability with a peak near the resting membrane potential of PVSMC. In conclusion, these findings highlight differences between the contractile properties of veins and arteries and reveal a significant contribution of Ca2+ influx and an NFA-sensitive conductance during venous contraction to agonists and hypoxia. Furthermore, the results suggest that a novel hypoxia-sensitive KV current contributes to membrane potential under resting conditions in PVSMC and its inhibition by hypoxia may contribute to the initiation of HPV in porcine intrapulmonary veins.
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Lim, Ta. "The role of hypoxia-inducible factor-1α in xenon preconditioning versus hypoxic-ischaemic organ injury". Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/7663.
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Background: The anaesthetic gas xenon provides long-lasting preservation of neuronal function when given several hours prior to neuronal injury. This phenomenon is described as preconditioning. However, little is known of the mechanisms by which xenon preconditioning mediates its protective effect. Interest has focused on the involvement of hypoxia-inducible factor-1α (HIF-1α) in preconditioning because: (i) Hypoxia activates HIF-1α and is an effective preconditioning stimulus; (ii) HIF-1α is a regulator of adaptive responses promoting cellular survival; (iii) Several genes that have hypoxia-responsive elements (HRE) for HIF-1 in the promoter region are capable of mediating preconditioning (e.g., erythropoietin). Therefore, this study speculates on the role of HIF-1α in xenon preconditioning. Method: Separate cohorts of male adult C57/BL6 mice were preconditioned by exposure to 75% xenon/25 % oxygen for 2 hours and thereafter immediately sacrificed for organ harvesting at 0-24 hours after xenon preconditioning. Semi-quantitative study of HIF-1α and EPO protein expression was performed by Western blot analysis, and RT-PCR was used as a measure of gene transcription. Results: Xenon preconditioning provokes a time-dependent increase in HIF-1α protein in brain as well as kidney. Xenon preconditioning also caused a time-dependent increase in EPO (a HIF-1 target gene) transcription and protein expression in a corresponding time course to xenon-induced HIF-1α. To elucidate the mechanisms of xenon-induced HIF-1α accumulation, the effect of xenon preconditioning on HIF-1α transcription, translation and degradation was studied. Xenon preconditioning does not induce a change in HIF-1α mRNA expression, nor does it significantly attenuate the expression of the PHD2 enzyme, required for HIF-1α degradation. To explore translation-dependent pathways, mice were treated with rapamycin before xenon preconditioning, to inhibit translation of HIF-1α through the mTOR pathway. Inhibition of this pathway prevented the xenon-induced increase of HIF-1α protein. To ascertain whether HIF-lα is required for xenon preconditioning, siRNA was used to knockdown HIF-lα expression in the kidney and xenon's renoprotective properties were shown to be abolished. Conclusions: Over the same time course as xenon's protection against subsequent injury in both brain and kidney, xenon preconditioning induces expression of HIF-1α. Increased HIF-1α expression is also associated with increased activity as evidenced by enhanced transcription and translation of the downstream effector, EPO. Xenon preconditioning does not regulate HIF-1α at the transcriptional level, nor does it inhibit HIF-lα degradation. However, these results suggest that xenon preconditioning upregulates expression of HIF-1α through translation-dependent mechanisms. Furthermore, xenon's action on HIF-1α is shown to be causally related to its organ protective effect. If these data can be extrapolated to the clinical setting, exposure to xenon would be beneficial prior to procedures in which organ perfusion is interrupted, preventing hypoxic-ischaemic as well as ischaemic-reperfusion injury.
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Hsieh, Yee-Hsee. "BRAINSTEM GABAA RECEPTOR SHAPE THE RESPONSE AND ADAPTATION TO HYPOXIA." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1184267396.
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Lau, Chi-keung. "Blockade of hypoxia inducible factor-1[alpha] sensitizes hepatocellular carcinoma to hypoxia and chemotherapy." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B39634243.
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Hägg, Maria. "Hypoxia-inducible factors (HIFs) and biological responses in hypoxia, inflammation and embryonic vascular development /." Göteborg: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, 2008. http://hdl.handle.net/2077/9991.
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Nakhlé, Jessica. "Rôle de la thrombospondine-1 dans la migration, l’invasion et la dissémination métastatique dans les carcinomes prostatiques et mammaires." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T088/document.
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Les métastases représentent l’étape ultime de la progression tumorale. Les traitements inhibiteurs de l’angiogenèse offrent de nouvelles perspectives thérapeutiques, notamment pour les stades invasifs, mais cependant ils n’apportent qu’une prolongation modeste de la survie des patients. La faible réponse de certains types de cancers aux traitements ciblant l’angiogenèse tumorale, comme le carcinome de la prostate chez l’homme ou du sein chez la femme, est due au développement de résistances tumorales d’une part, et à l’accélération du processus métastatique mise en évidence par certaines études précliniques et cliniques d’autre part. L’objectif de ce travail de thèse a été d’étudier le rôle d’une protéine anti-angiogénique endogène, la thrombospondine 1 (TSP1), dans l’invasion et la dissémination métastatique dans le carcinome de la prostate et du sein. Notre laboratoire a montré que la densité microvasculaire est inversement corrélée à l’expression de la TSP1 dans les stades précoces de ces carcinomes. Cependant, cette corrélation est perdue aux stades avancés où l’expression de la TSP1 devient associée à un mauvais pronostic. Les travaux de ma thèse ont permis de montrer que la TSP1 stimule un ensemble de processus intervenant dans la progression tumorale, dont la migration et l’invasion cellulaires, l’extravasation et la dissémination métastatique. Nous avons aussi pu mettre en évidence que l’hypoxie induite par l’inhibition de l’angiogenèse est un activateur majeur de l’invasion et de la formation de métastases, que cette hypoxie soit produite par des molécules endogènes comme la TSP1 ou par des inhibiteurs pharmacologiques de ce processus. De plus, nous démontrons que la TSP1 est un facteur de mauvais pronostic puisque son expression est corrélée avec l’augmentation de l’invasion et de la rechute des patients atteints de cancers de la prostate androgéno-résistants. En conclusion, nos résultats suggèrent que l’expression de la TSP1 pourrait être un facteur prédictif de l’invasion et de l’occurrence de métastases, et que le ciblage de la TSP1 présente un fort potentiel thérapeutique pour bloquer à terme ces processus<br>Prognosis is poor once tumors developed metastasis, and overall survival has been only modestly improved by the development of drugs inhibiting angiogenesis. The poor response of certain types of cancer to therapies that target tumor angiogenesis, including prostate and breast carcinomas, is due to the development of an evasion and to the acceleration of the metastatic process noted in some preclinical and clinical studies. The objective of this thesis was to study the role of an endogenous anti-angiogenic factor, thrombospondin 1 (TSP1), in the process of invasion and metastasis of prostate and breast carcinomas. Our laboratory has previously shown that microvessel density is inversely correlated with the expression of TSP1 in primary stages of breast and prostate carcinomas. However, this correlation is lost in advanced cancers, where TSP1 expression becomes associated with poor prognosis. We show that TSP1 stimulates a set of processes involved in tumor progression, including cell migration and invasion, extravasation and metastatic dissemination. We also demonstrate that hypoxia induced by an inhibition of angiogenesis resulting from the activity of endogenous or pharmacological molecules is a major activator of invasion and metastasis. In addition, we demonstrate that TSP1 is a poor prognostic factor since its expression is correlated with increased invasion and relapse in patients with androgen-resistant prostate cancer. In conclusion, our results suggest that the expression of TSP1 could be a predictor of invasion and metastasis occurrence, and that targeting TSP1 could be a great therapeutic potential to block these processes
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Mordel, Patrick. "Variabilité glycémique : exploration in vitro des fonctions cellulaires et mitochondriales sur la lignée de cardiomyocyte HL-1." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMC415/document.
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Le diabète est associé à une augmentation de risque de maladie cardiovasculaire et une dérégulation du métabolisme. Il a été suggéré que la variabilité glycémique (VG) pouvait avoir un rôle dans le développement des complications du diabète. Afin d’étudier et de caractériser les dysfonctions induites par la VG, nous avons mis au point un modèle in vitro mimant la VG sur la lignée de cardiomyocytes HL-1. Nous avons ainsi développé un traitement de 12 heures, mimant hypoglycémie, normoglycémie, hyperglycémie et VG. L’étude de la signalisation cellulaire ne nous a pas permis de montrer un rôle délétère de la VG. Nous avons toutefois mis en évidence que la VG participait à des dysfonctions mitochondriales. En effet en situation de fluctuations en glucose, les mitochondries des cellules HL-1 présentent une augmentation de leur potentiel de membrane, ainsi qu’une augmentation de la production d’anions superoxydes. Bien que nous n’ayons pas réussi à montrer de perturbation de la chaîne respiratoire après 12 heures d’exposition, nous avons pu montrer que 72 heures d’exposition provoquaient une baisse de la respiration mitochondriale. Nous avons enfin étudié l’impact des fluctuations en glucose sur la susceptibilité au développement de lésions d’hypoxie, et avons montré que les lésions sont majorées après 36 heures d’hypoxie en cas d’exposition à des fluctuations en glucose. Nos résultats montrent un rôle délétère de la VG, néanmoins des expériences complémentaires sont nécessaires afin de caractériser de manière plus précise les mécanismes impliqués<br>Diabetes mellitus is associated with higher risk of cardiovascular disease and metabolism dysregulation. Glycemic variability (GV) has been suggested as a risk factor in diabetic complication. In order to characterize dysfunctions induced by GV, we developed an in vitro model that transpose GV on the cardiac cell line HL-1. We exposed our cells to a treatment of 12 hours miming hypoglycemia, normoglycemia, hyperglycemia and GV. The exploration of signaling pathways didn’t allow us to show a deleterious effect of glucose fluctuation. However we were able to point mitochondrial alteration under glucose fluctuation. HL-1 cells mitochondria exhibit a higher membrane potential and an increase of superoxide anion production. Although we didn’t show any alteration in mitochondrial respiration after 12 hours of exposition, we showed that after 72 hours of glucose fluctuation, HL-1 cells showed a decrease in mitochondrial respiration. We finally studied the impact of glucose fluctuation on the susceptibility to develop hypoxic injuries. We showed that after 36 hours of hypoxia, injuries were higher for cells exposed to glucose fluctuation. Our results indicate a deleterious effect of GV, but additional experiments are needed to better characterize the mechanisms
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Wahlquist, Hanna. "Hypoxia and Angiogenesis in IUGR." Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9316.
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<p>BACKGROUND: Intrauterine growth restriction (IUGR) is a condition where the infant fails to reach its genetic growth potential due to numerous factors. IUGR foetuses are associated with high perinatal mortality and morbidity. This study investigated if hypoxia might be involved during gestation, and whether if hypoxia may have an impact on the development of the placenta, through regulation of various angiogenic factors, such as HIF-1_, VEGF, PIGF, VEGFR-1 and CD31. METHOD: Each sample of placental tissue was stained by immunohistochemisty for HIF-1_, VEGF, PIGF, VEGFR-1 and CD31. The intensity of staining was graded and the difference between the normal term placentas and the IUGR term placentas were evaluated. RESULTS: HIF-1_ was found to be upregulated in the normal term placental tissue, and VEGFR-1 was found to be upregulated in the IUGR term placental tissue. The other antibodies did not show any significant difference and PIGF failed to show any positive staining. CONCLUSIONS: Further studies on hypoxia in IUGR would be beneficial.</p>
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Hobbs, Catherine E., and n/a. "Perinatal hypoxia-ischaemia : neuroprotective strategies." University of Otago. Department of Anatomy & Structural Biology, 2005. http://adt.otago.ac.nz./public/adt-NZDU20070221.145910.
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Perinatal hypoxia-ischaemia is a major cause of disability, including cerebral palsy, yet a neuroprotectant which fully protects the brain remains elusive. Following a hypoxic-ischaemic insult, striatal medium-spiny neurons and hippocampal CA1 neurons are vulnerable to a complex cascade of neurotoxic events. This cascade includes energy failure, a massive release of glutamate, the formation of free radicals and caspase activation. The overall aim of this thesis was to assess the efficacy of three potential neuroprotective strategies that target this cascade from different directions. Short-term, and where appropriate, long-term, neuroprotection was investigated. The first treatment strategy aimed to suppress the generation of free radicals through treatment with the potent free radical spin trap, N-tertbutyl-(2-sulphophenyl)-nitrone (S-PBN). The second compound tested was the caspase-3 inhibitor, minocycline. Finally, the third treatment strategy combined a series of S-PBN injections with 6 hours of moderate hypothermia immediately after hypoxia-ischaemia. Hypothermia is suggested to slow the rate of the neurotoxic cascade, thus potentially allowing other neuroprotective agents greater efficacy.
Using an adaptation of the Rice et al. (1981) model, hypoxia-ischaemia was induced on postnatal day (PN) 8 in the right cerebral hemisphere. For the short-term studies, the rats were perfused at 14 days-of-age. The brains were dissected out and embedded in Technovit. Forty [mu]m serial sections were cut through the right striatum and hippocampus. The total number of medium-spiny neurons in the striatum and where appropriate, the total number of neurons in the hippocampal CA1 pyramidal layer, were stereologically determined using the optical disector/Cavalieri method.
For the long-term study, fine motor control was assessed in half of the animals through the staircase test from 9-11 weeks-of-age. Neuroprotection was assessed in the remaining animals. All animals were sacrificed at 12 weeks-of-age. The total number of striatal medium-spiny neurons was stereologically determined in the non-behavioural animals as described above.
A series of seven injections of S-PBN (100mg/kg) did not offer statistically significant neuroprotection to the striatum at one week after perinatal hypoxia-ischaemia. Similarly, a single injection of minocycline (45mg/kg) immediately after the insult did not offer significant neuroprotection to the striatum nor the CA1 region of the hippocampus at this early time-point. In contrast, when the series of S-PBN injections was combined with 6 hours of moderate hypothermia post-hypoxia-ischaemia, sterelogical analysis revealed significant neuroprotection of the striatal medium-spiny neurons to normal levels at one week after the injury. No significant neuroprotection was seen in the CA1 region of the same animals.
To assess whether this impressive striatal neuroprotection was long-lasting and whether it represented functional rescue, the final experiment in this thesis investigated rat pups at 12 weeks-of-age after exposure to hypoxia-ischaemia at PN8. Treatment with S-PBN/hypothermia offered persistent neuroprotection of striatal medium-spiny neurons and preservation of fine motor skills compared to diluent-normothermia-treated controls. The long-term behavioural outcomes were compared with normal, uninjured controls and the total number of medium-spiny neurons was compared with normal numbers from the literature. These comparisons revealed that the histological and functional integrity of the striatum was rescued to normal levels.
This is the first study to identify a treatment strategy that offers complete and long-lasting preservation of striatal neuronal numbers, by accurate and unbiased stereological methods, paired with persistent preservation of fine motor control following perinatal hypoxia-ischaemia.
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Raval, Raju R. "Hypoxia-mediated pathways in cancer." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433331.
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Talbot, Nicholas. "Pulmonary vascular responses to hypoxia." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404270.
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Peansukmanee, Siriporn. "Equine chondrocyte metabolism under hypoxia." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501589.
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The avascular nature of articular cartilage limits oxygen supply within the tissue. Cartilage, therefore, is under physiological hypoxic conditions. Oxygenation gradients are estimated from 10% at the surface to 1% at the deepest layer. Nonetheless, chondrocytes have been reported to be able to survive and are well-adapted to such an environment. We hypothesised that low oxygen tensions favour chondrocyte metabolism based on their nature and literature reviews.
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MacManus, Michael Patrick. "Erthropoietin, anaemia and tumour hypoxia." Thesis, Queen's University Belfast, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335941.
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Jones, Richard David. "Hypoxia and the pulmonary circulation." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301608.
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Padmanabha, Divya. "HIF-INDEPENDENT RESPONSES IN HYPOXIA." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3828.
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The adaptive response to hypoxia is accompanied by widespread transcriptional changes that allow for prolonged survival in low oxygen. Many of these changes are directly regulated by the conserved hypoxia-inducible factor-1 (HIF-1) complex; however, even in its absence, many oxygen-sensitive transcripts in Caenorhabditis elegans are appropriately regulated in hypoxia. To identify mediators of these non-HIF-dependent responses, I established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (cobalt chloride). The reporter is selective and HIF-independent, in that it remains insensitive to a number of cellular stresses, but is unaffected by mutation of the prolyl hydroxylase egl-9, suggesting that the regulators of this response pathway are different from those controlling the HIF pathway. I used the HIF-independent reporter to screen a transcription factor RNAi library and identified genes that are required for hypoxia sensitive and cobalt chloride-induced GFP expression. Three mediators of the HIF-independent response zinc finger protein BLMP-1, chromatin remodeling factor LIN-40, and T-box transcription factor TBX-38 were isolated as mediators of the HIF-independent response. First, we show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 it is required for appropriate hypoxic-induced expression of HIF-independent transcripts. Further, we demonstrate that BLMP-1 is necessary for an increase of hypoxia-dependent histone acetylation within the promoter of a non-HIF-dependent hypoxia response gene. Additionally, we explore BLMP-1’s role in two hypoxia-regulated physiological processes namely unfolded protein response and collagen formation. We also briefly investigate the role of LIN-40 in the hypoxia response.
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Lungu, Gina Florentina. "Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3082.
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Borecky, Lisa. "Hypoxia-inducible factor-1α and the Control of Hypoxic Ventilatory and Metabolic Responses in Mice and African Naked Mole Rats". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37908.
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Hypoxia-inducible factors (HIFs) are a highly conserved group of transcriptional regulators responsible for cellular and systemic O2 homeostasis in animals. However, how HIFs are involved in basic adaptive ventilatory and metabolic responses to acute and chronic hypoxia remains incompletely characterized. Naked mole rats are among the most hypoxia tolerant mammals identified. As opposed to the typical hyperventilatory response of most adult mammals, naked mole rats exhibit a unique decline in ventilation, matching their substantial decrease in metabolic rate. Naked mole rats therefore provide an excellent model in which to investigate adaptations to hypoxic ventilatory and metabolic responses (HVR and HMR, respectively). Interestingly, naked mole rats possess a mutation within the von Hippel-Lindau (VHL) binding domain—a protein necessary for proteasomal degradation of HIF subunits in normal O2 concentrations—suggesting they retain elevated baseline expression of HIF and thus an upregulation of downstream gene targets. In designing our experiment, we focused on sustained hypoxia and HIF1, which is typically the first responder subunit upon exposure to low O2 stress. We sought to determine how increased HIF1 expression might contribute to the distinct HVR and HMR of naked mole rats, first by confirming the observed VHL mutation translates into increased HIF1 protein expression via immunoblotting. HIF1 protein expression was found to be 3-fold higher in naked mole rat brain than mouse brain and 4-fold higher than in mouse liver tissue (p < 0.05). We then investigated how elevated HIF1 levels might contribute to the HVR and HMR by treating naked mole rats with two different HIF1 inhibitors (either echinomycin; 0.5 and 1.0 mg kg-1, or PX-478; 80.0 mg kg-1) and subsequently examined changes in ventilatory and metabolic parameters in awake animals exposed to sustained hypoxia (7% O2; 1 hour). In control naked mole rats, minute ventilation (V̇E) reversibly decreased by 32% in hypoxia (1298.3 ± 188.5 to 882.6 ± 117.0 mL min-1 kg-1) because of changes in both breathing frequency (fR) and tidal volume (VT). Conversely, the HVR was not significantly affected in any of our three treatment groups however, normoxic ventilation increased in naked mole rats treated with low dose echinomycin (0.5 mg kg-1) by 72% (from 1298.3 ± 188.5 to 2239.5 ± 221.1 mL min-1 kg-1). Consistent with previous findings, metabolic rate in control naked mole rats decreased 70% (from 40.1 ± 5.0 to 11.9 ± 0.9 mL O2 min-1 kg-1). Again, treatment with our pharmacological agents did not significantly alter this response but did result in a 43% decrease in basal metabolic rate (V̇O2 and V̇CO2) in both high-dose echinomycin and PX-478 treated naked mole rats (40.1 ± 5.0 to 22.5 ± 3.6 and 23.0 ± 1.88 mL O2 min-1 kg-1 respectively, p < 0.05), dulling the magnitude of the HMR. As a result of unmatched changes in V̇E and V̇O2, HIF1 deficient naked mole rats treated with both low-dose echinomycin and PX-478 experienced an atypical increase in their air convection requirement (ACR; V̇E:V̇O2-1) in hypoxia (from 77.4 ± 11.3 to 159.2 ± 34.63 and 123.5 ± 35.5 respectively, p < 0.05), resembling a hyperventilation response closer to that of hypoxia-intolerant mammals.
To further determine how increased HIF1 availability affects the HMR and HVR, we administered hypoxia-intolerant mice with a pharmacological HIF1 agonist (3,4- EDHB; 180 mg kg-1) and used identical experimental design to measure downstream ventilatory and metabolic responses. Mice exhibit similar reductions in metabolic rate during hypoxic exposure (from 60.3 ± 2.4 to 21.8 ± 1.8 mL O2 min-1 kg-1, p < 0.05) but experience a 30% increase in fR (from 157.5 ± 9.5 to 200.4 ± 10.8 breaths min-1, p < 0.05). In contrast, mice treated with EDHB and to exposed 7% O2 exhibited a 20% increase in fR (200.4 ± 10.8 to 236.5 ± 14.1 breaths min-1, p < 0.05) and a 30% reduction in the magnitude of their HMR (from 38.5 ± 2.8 to 27.8 ± 3.6 ΔV̇O2). No other significant trends were observed in any of the other parameters measured. We conclude metabolic and ventilatory control in naked mole rats and mice may partially depend on increased HIF1 expression.
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Pawar, Anita. "Intermittent Hypoxia and Neonatal Carotid Body Function." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1237993899.
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Anduran, Emilie. "Bioreductive Activated Prodrugs to Target Tumor Hypoxia." Electronic Thesis or Diss., Montpellier, Ecole nationale supérieure de chimie, 2022. https://theses.enscm.fr/ENSCM_2022_ANDURAN.pdf.
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L'hypoxie est une caractéristique bien connue du microenvironnement dans les tumeurs solides, associée à l'agressivité, aux métastases et à un impact négatif sur le pronostic thérapeutique. Les tumeurs hypoxiques sont généralement résistantes à la radiothérapie et à la chimiothérapie. Considérant son rôle central dans la progression tumorale et la résistance au traitement, l'hypoxie tumorale est considérée comme une cible validée à exploiter en oncologie pour développer des outils diagnostiques et thérapeutiques. Les différences significatives entre le microenvironnement hypoxique et les tissus normaux offrent une opportunité thérapeutique grâce à la conception de promédicaments activés par hypoxie bioréductrice (PAD). Le but de ce projet est d'étudier (conception, synthèse, caractérisation et activité biologique) une nouvelle version HAP des agents utilisés dans le traitement systémique, y compris l'immunothérapie. La stratégie sera basée sur l'approche HAP permettant de nouveaux agents antitumoraux conçus pour libérer ou activer des thérapeutiques ciblées dans les régions hypoxiques des tumeurs, offrant une plus grande sélectivité et une toxicité plus faible que les agents anticancéreux existants, complétant ainsi les approches actuelles d'immunothérapie et de radiothérapie<br>Hypoxia is a well-known feature of the microenvironment in solid tumors, associated with aggressiveness, metastases and a negative impact on therapeutic prognosis. Hypoxic tumors are generally resistant to radiotherapy and chemotherapy. Considering its central role in tumour progression and resistance to therapy, tumour hypoxia is considered as a validated target to be exploited in oncology to develop diagnostic and therapeutic tools. The significant differences between the hypoxic microenvironment and normal tissues, offer a therapeutic opportunity through the design of bioreductive hypoxia-activated prodrugs (HAPs). The goal of this project is to investigate (design, synthesis, characterization and biological activity) a novel HAP version of agents used in systemic treatment including immunotherapy. The strategy will be based on HAP approach allowing new antitumoral agents designed to release or activate targeted therapeutics within hypoxic regions of tumors, offering greater selectivity and lower toxicity than existing anticancer agents, also complementing current immunotherapy and radiotherapy approaches
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Huey, Kimberly A. "Time-dependent changes in dopamine D₂-receptor modulation of the hypoxic ventilatory response with chronic hypoxia /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9935485.
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Knight, Laura K. "The effect of hypoxia and the transcription factor hypoxia inducible factor-1 (HIF-1) on metastasis." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502269.
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Tumour hypoxia has been widely implicated in the development of aggressive, therapy resistant malignant disease. Patients presenting with more hypoxic tumours experience higher levels of mortality compared to those with lower levels of hypoxia. The primary reason or this increased phenotype is the stabilisation of the transcription factor hypoxia inducible factor-1 (HIF-1). Upon exposure to hypoxic conditions, the alpha subunit of this heterodimer Stabilised and binds to the beta subunit. Once stabilised HIF-1 induces gene expression resulting in the Increased exproression of a number of proteins that confer advantages onto tumour cells. Areas such as angiogenesis, glucose metabolism, invasion and metastasis are tumour cells. Areas such as angiogenesis, glucose metabolism, invasion and metastasis are widely influenced in this way. In the following studies, the role of HIF-1 in the development of metastatic disease was examined.
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Lim, Ai Lin. "Characterization of hypoxia-induced gene (HIG2) and hypoxia-inducible autophagy as novel pathways of tumor growth /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Taheem, Dheraj Kumar. "A role for hypoxia and hypoxia inducible factor during chondrogenesis of bone marrow mesenchymal stem cells." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/a-role-for-hypoxia-and-hypoxia-inducible-factor-during-chondrogenesis-of-bone-marrow-mesenchymal-stem-cells(8f516122-6cd6-4c9b-91f6-bede34427fd5).html.
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Articular cartilage lesions cause pain, morbidity and may progress to osteoarthritis, which in terms of medical care, has been approximated to cost 1-2.5% of the gross national product of USA, UK, France and other countries. Current repair strategies have considerable limitations and have prompted the development of cartilage tissue engineering (CTE) approaches. One of the challenges of CTE is the expansion and differentiation of adult stem cells in vitro, into functional articular chondrocytes whilst avoiding hypertrophy. Hypoxia is an important environmental factor required for cartilage development, for stimulating articular chondrogenesis and ECM formation. There remains, however, a number of questions regarding the in vitro role of hypoxia and HIF stabilization in the development of CTE strategies. These include: a) the appropriate level of hypoxia required for chondrogenesis, b) determining if artificial HIF stimulation has advantages over physiological hypoxia, c) which of the commonly-used HIF-stimulating compounds most potently induces HIF-mediated articular chondrogenesis and d) if there exists a relationship between mechanostransduction and HIF during chondrogenesis. Compared to normoxia, hypoxia (2%O2 and 5%O2) induced the expression HIF target genes (including VEGFA, PGK1 and EGLN) but only 5% inhibited hypertrophic collagen type X expression. Artificial stimulation of HIF-1a by DMOG induced greater expression of HIF chondrogenic targets (SOX9 and collagen-modifying enzymes) than other compounds used (CoCl2 and DFX) and physiological hypoxia. DMOG also reduced collagen type X at the mRNA level compared to the other HIF stabilising compounds. In terms of the effect of hypoxia on mechano-signalling during chondrogenesis, exposure to 2%O2 induced ROCK activity, actin re-organisation and SOX9 expression during BM-MSC chondrogenesis on soft polyacrylamide gels. No such changes were induced on stiff substrates. This suggests the existence of specific crosstalk between HIF and stiffness-sensing pathways, which may inform CTE strategies in which hypoxia-mediated chondrogenesis of BM-MSCs is conducted within biomaterial scaffolds of a defined stiffness.
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Adhami, Faisal. "Differential Adult and Neonatal Response to Cerebral Ischemia-Hypoxia." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196054266.
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Otandault, Aviviani Amaelle Cherone. "ADN circulant nucléaire et mitochondrial et étude de l'influence de l'hypoxie sur leur libération." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT011.
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Plusieurs travaux s’accordent sur le fait que l’analyse de l’ADN circulant (ADNcir) est un outil à fort potentiel diagnostic, pronostic, théranostic et de suivi en oncologie clinique. Cependant, le manque de standardisation des procédures pré-analytiques, des connaissances approfondies des structures des ADNcir ainsi que les facteurs influençant la dynamique de son relargage constituent des obstacles à son transfert en pratique clinique. C’est dans ce contexte que nous avons choisi d’approfondir l’étude des structures des ADNcir d’origines nucléaire et mitochondriale, évaluer leur utilité clinique en oncologie et étudier l’effet de l’hypoxie sur leur libération. A partir d’une technique de qPCR optimisée et validée cliniquement pour l’analyse des ADN circulants, nous avons quantifié les ADN extracellulaires d’origines nucléaire et mitochondriale dans des milieux de culture cellulaire et dans des plasmas humains et murins.Nos données ont révélé l’influence des procédures pré-analytiques sur la quantification de l’ADN circulant en fonction de l’origine. En effet, nous montrons que la préparation du plasma par séparation en ficoll diminue de manière significative la quantification de l’ADNcir d’origine mitochondriale sans influencer la quantification de l’ADNcir d’origine nucléaire, ce qui suggère la présence de structures de densité différente contenant de l’ADN mitochondrial dans le plasma. D’autre part, j’ai contribué à l’évaluation d’un test de dépistage du cancer basé sur l’analyse de l’ADNcir nucléaire et mitochondrial mise au point au laboratoire. Nos résultats préliminaires montrent de façon significative la capacité diagnostic de ce test sur des cohortes de patients atteints de cancers colorectal (n = 127) versus des individus sains (n = 91) (AUC = 0,8657 ; p < 0,0001).Nous montrons in vitro que l’hypoxie module de manière différente le relargage des ADN extracellulaires en fonction de leur origine, et notamment que l’ADN extracellulaire d’origine mitochondriale semble être régulé négativement en condition hypoxique. In vivo, l’hypoxie entraîne une augmentation de la libération de l’ADNcir d’origine nucléaire (p=0,002), mais pas d’origine mitochondriale, dans le plasma de souris greffées avec des cellules tumorales de cancer de poumon.Pour conclure, les travaux réalisés au cours de cette thèse mettent en lumière : (i) l’intérêt de la mise en place de procédures pré-analytiques standardisées pour la compréhension des origines et structures des ADNcir ; (ii) le fort potentiel diagnostic de l’analyse de l’ADNcir en oncologie ; (iii) et l’influence de l’hypoxie sur le relargage de l’ADN circulant<br>Different studies converge on the diagnostic, theragnostic and prognostic properties of circulating DNA analysis (cirDNA) in clinical oncology. There remain various obstacles, however, to its transfer to clinical practice. These include the lack of standardization of pre-analytical procedures, and limited knowledge of cirDNA structures and of the factors influencing the dynamics of their release. In this context, we studied the structures of cirDNA of nuclear and mitochondrial origins, evaluated their diagnostic potential, and then evaluated the effect of hypoxia on their release. Using an optimized qPCR technique previously validated in clinical studies for the analysis of cirDNA, we quantified extracellular DNA of nuclear and mitochondrial origins in cell culture medium and in human and mouse plasma.Our data also revealed the influence of pre-analytical procedures on the quantification of cirDNA, depending on its origin. Indeed, we showed that plasma preparation with Ficoll separation significantly reduces the quantification of mitochondrial cirDNA without influencing the quantification of nuclear cirDNA.In addition, we evaluated the value of nuclear and mitochondrial cirDNA analysis in a cancer-screening test developed in the laboratory. Our preliminary results demonstrated a significant discrimination between colorectal cancer patients (n=127) and healthy individuals (n=91) (AUC=0.8657; p<0.0001).We demonstrated that in vitro hypoxia modulates the release of extracellular DNA in different ways, depending on its origin, and showed that extracellular DNA of mitochondrial origin is negatively regulated. By contrast, we demonstrated in vivo that hypoxia leads to a greater release of nuclear cirDNA (p=0.002), but not of mitochondrial cirDNA, as compared to normoxia. These experiments were performed using the plasma of mice grafted with lung cancer tumor cells.In conclusion, the work carried out for this thesis highlights: (i) the importance of setting up standardized pre-analytical procedures when investigating the origins and structures of cirDNA; (ii) the strong diagnostic potential of cirDNA analysis in oncology and (iii) the influence of hypoxia on the release of cirDNA
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Tan, Qiulin. "Inhibition of cholesterol biosynthesis under hypoxia." Texas A&M University, 2005. http://hdl.handle.net/1969.1/3101.
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Oxygen balance is very important and tightly regulated in mammals. Under
hypoxia, hypoxia inducible factor 1(HIF-1) dimerizes with hypoxia inducible
factor 1± (HIF-) and activates expression of several genes. Using a
mammalian two hybrid assay, we found that HIF-1 interacted with sterol
response element binding protein 1a (SREBP1a). SREBP1a regulates
transcription of HMG-CoA reductase via binding to the sterol response element
(SRE) in the promoter region. HMG-CoA reductase is the rate-limiting enzyme in
cholesterol biosynthesis. The interaction between SREBP1a and HIF-1suggests that HIF-1 may play an important role in regulation of cholesterol
biosynthesis. We tested the effects of hypoxia on the HMG-CoA reductase. We
found that hypoxia caused suppression of SRE-driven luciferase reporter gene
expression. HMG-CoA reductase mRNA levels decreased under hypoxia in both
hepatoma cells and mouse primary hepatocytes. Electrophoretic mobility shift
assay showed that HIF-1 blocked binding of SREBP1a to the SRE sequence in
vitro. Ectopic expression of HIF-1 suppressed the SRE- driven luciferase
reporter gene expression in BPR cells (HIF-1). Our results suggest that
hypoxia inhibits cholesterol biosynthesis by suppressing SREBP1a-regulated gene expression and this suppression is caused by the blockage of SREBP1a
binding to SRE sequence by HIF-1.
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Hoenderdos, Kim. "Modulation of neutrophil degranulation by hypoxia." Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/247459.
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Neutrophils are key effector cells of the innate immune system. They employ a number of powerful ‘weapons’ to eliminate pathogens, including an array of destructive proteins packaged into distinctive granule subsets. In addition to their microbicidal activity, these granule proteins are capable of causing substantial tissue damage if inappropriately deployed. To mitigate against this possibility, most physiological stimuli induce minimal extracellular degranulation. Sites of inflammation and infection are usually hypoxic, and it has been shown that oxygen depletion compromises neutrophil function by impairing the generation of reactive oxygen species and hence bacterial killing. The key finding reported in this thesis is that hypoxia substantially increases the release of all neutrophil granule subsets, as measured by the release of (active) hallmark proteins (elastase, myeloperoxidase, lactoferrin and matrix metalloproteinase-9). In consequence, supernatants from hypoxic neutrophils induced substantially more damage to lung epithelial cell layers than supernatants from neutrophils cultured under normoxic conditions; this damage was protein- and protease-dependent. This pattern of damage was seen consistently across lung adenocarcinoma-derived epithelial cells, primary immortalised lung epithelial cells, and primary human bronchial epithelial cells grown in physiological air-liquid interface culture. Surprisingly, the mechanism of hypoxia-augmented degranulation was found to be independent of protein synthesis and specifically, of the transcription factor HIF-1α (the ‘master-regulator’ of hypoxic responses); thus, hypoxia did not affect mRNA transcript or protein abundance of the major granule components, and hypoxia mimetics failed to recapitulate the phenotype. Inhibition of the key pathways known to be involved in neutrophil degranulation, including, phosphatidylinositol 3-kinase and phospholipase C, but not calcium flux prevented augmented granule release under hypoxia In conclusion, hypoxia induces a destructive neutrophil phenotype, with increased release of multiple histotoxic proteases. This may contribute to tissue injury and disease pathogenesis in a range of clinically important conditions.
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Winter, Stuart Charles Alec. "Hypoxia in head and neck cancer." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428506.
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Eckert, Danny Joel. "Hypoxia suppresses sympton perception in asthma /." Title page and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09SB/09sbe1918.pdf.
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Sluimer, Judith Christina. "Hypoxia, HIF and angiogenesis in atherosclerosis." Maastricht : Maastricht : Universitaire pers Maastricht ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=10707.
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Soo, Catherine Chun-Yan. "Hypoxia in inflammation : potential therapeutic target." Thesis, Queen Mary, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313350.
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50
Li, Jingping, and 李京平. "Role of tissue hypoxia in periodontitis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47849563.
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In periodontitis, local oxygen supply and consumption in gingival tissues may be
significantly altered due to the inflammatory process. The etiology agent of
periodontal disease i.e. anaerobic bacterial biofilm is known to confer a low
oxygen tension in the vicinity of periodontitis lesion. The oxygen shortage will
lead to the stabilization of HIF-1α, the regulatory subunit of hypoxia-inducible
factor (HIF)-1, which through controlling specific downstream genes transcription
may modulate multiple cellular functions and hence shape the process of
periodontitis. Lipopolysaccharide (LPS), a cell wall component of anaerobic
bacteria, has been considered to be involved in the pathogenesis of periodontitis. Its
interaction with host peptides including LPS-binding protein (LBP), CD14, MD-2
and Toll-like receptor (TLR) 4 may trigger the production of inflammatory
cytokines.
In this project we hypothesize that hypoxia and bacterial components may induce
HIF-1α activity, which in turn impacts upon on the pathological process of
periodontitis. This project aimed to detect in vivo expression of HIF-1α and TLR4
in human gingivae; to examine whether LPS could induce HIF-1α activity through
pattern recognition receptor like TLR4 on human primary gingival fibroblasts
(HGF); and to investigate the combined effect of hypoxia and LPS on type I
collagen metabolism in HGF.
Human gingival biopsies were collected from advanced periodontitis or clinically
healthy sites. By immunohistochemistry, both HIF-1α and TLR4 peptides
appeared to express in gingival epithelium. In periodontal pockets, there appeared
a marked increase in HIF-1α and TLR4 expression in fibroblast-like and
leukocyte-like cells.
Human primary gingival keratinocytes (HGK) and fibroblasts (HGF) were
cultured. Transcripts of TLR4, MD-2 and CD14 were identified in HGK, HGF
and periodontal tissue using RT-PCR. Their protein products were identified in
both cell types in vitro using immunoblotting. LBP transcript was only found in
gingival biopsies but not in HGK and HGF culture.
HGF treated by Escherichia coli LPS ranging from 0.2 μg/mL to 200 μg/mL
showed nuclear accumulation of HIF-1α peptide, detectable by
immunocytofluorescence and immunoblotting. This accumulation could be
attenuated by treatment with TLR4-neutralizing antibody. Under hypoxia, LPS
further increased HIF-1α accumulation. Using quantitative real-time PCR (qPCR),
hypoxia and/or LPS appeared to enhance the transcription of certain enzymes or
enzyme subunits that are related to collagen assembly and crosslink, including
prolyl 4-hydroxylases, lysyl hydroxylases, lysyl oxidase and lysyl oxidase-like
enzymes. These increased transcription could be downregulated by pretreatment
with TLR4-neutralizing antibody or an HIF-α inhibitor,
3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1).
Finally, preliminary experiments showed KN-93 [Ca2+/Calmodulin-dependent
protein kinase (CaMK) II inhibitor] or cyclosporine-A (calcineurin inhibitor)
appeared able to attenuate the LPS-induced HIF-1α accumulation, indicating a
possible role for intracellular calcium signal in regulating HIF-1α.
In conclusions, human periodontitis is associated with increased expression of
TLR4 and HIF-1α in gingivae; hypoxia causes and LPS/TLR4 signal associate
with HIF-1α accumulation and activity in human gingival fibroblasts, and
subsequently modulate in a certain extend collagen metabolism through
upregulating the transcript expression of several collagen-related proteins. All
these implicate possibility of an adaptive physiological or pathological response
of human gingival fibroblasts towards gram-negative bacterial biofilm challenge
in human periodontium.<br>published_or_final_version<br>Dentistry<br>Doctoral<br>Doctor of Philosophy