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High-altitude exposures and intestinal barrier dysfunction.
McKenna, ZJ, Gorini Pereira, F, Gillum, TL, Amorim, FT, Deyhle, MR, Mermier, CM
American journal of physiology. Regulatory, integrative and comparative physiology. 2022;(3):R192-R203
Abstract
Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.
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Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics.
Packer, M
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(2):280-286
Abstract
Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney.
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Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.
Rock, CR, White, TA, Piscopo, BR, Sutherland, AE, Miller, SL, Camm, EJ, Allison, BJ
International journal of molecular sciences. 2021;(14)
Abstract
Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).
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The influence of carbohydrate ingestion on peripheral and central fatigue during exercise in hypoxia: A narrative review.
Paris, HL, Sinai, EC, Shei, RJ, Keller, AM, Mickleborough, TD
European journal of sport science. 2021;(10):1423-1435
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Abstract
Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.
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Reactive oxygen species as mediators of oxygen signaling during fetal-to-neonatal circulatory transition.
Villamor, E, Moreno, L, Mohammed, R, Pérez-Vizcaíno, F, Cogolludo, A
Free radical biology & medicine. 2019;:82-96
Abstract
Reactive oxygen species (ROS) are frequently seen as pathological agents of oxidative stress. However, ROS are not always deleterious and can also act as cell signaling molecules. Vascular oxygen sensing and signaling during fetal-to-neonatal circulatory transition is a remarkable example of the physiological regulatory actions of ROS. The fetal relative hypoxic environment induces hypoxic pulmonary vasoconstriction (HPV) and ductus arteriosus (DA) relaxation favoring the presence of high pulmonary vascular resistance and right-to-left ductal shunt. At birth, the increase in oxygen tension causes relaxation of pulmonary arteries (PAs) and normoxic DA vasoconstriction (NDAV), thus diverting blood flow to the lungs. Although the response to changes in oxygen tension is diametrically opposite, the mechanisms responsible for HPV and NDAV appear to be the result of a similar interaction between triggering and modulating factors that lead to an increase in cytosolic Ca2+ concentration and Ca2+ sensitization of the contractile apparatus. Growing evidence points to an increase in ROS (mitochondria- and/or NADPH-derived superoxide and/or H2O2), leading to inhibition of voltage-gated K+ channels, membrane depolarization, and activation of voltage-gated L-type Ca2+ channels as critical events in the signaling pathway of both HPV and NDAV. Several groups of investigators have completed this pathway adding other elements such as neutral sphingomyelinase-derived ceramide, the sarcoplasmic/endoplasmic reticulum (through ryanodine and inositol 1,4,5-trisphosphate receptors), Rho kinase-mediated Ca2+ sensitization, or transient receptor potential channels. The present review focus on the role of ROS as mediators of the homeostatic oxygen sensing system during fetal and neonatal life not only in the PAs and DA but also in systemic arteries.
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Metabonomics window into plateau hypoxia.
Chang, Y, Zhang, W, Chen, K, Wang, Z, Xia, S, Li, H
The Journal of international medical research. 2019;(11):5441-5452
Abstract
Oxygen deficiency in the plateau environment weakens aerobic metabolism and reduces the energy supply, leading to high-altitude diseases including decreased circulatory function, decreased nutrient and energy supply to tissues and organs, and decreased waste discharge. The involvement of many metabolic pathways is reflected in dramatic changes in levels of endogenous small molecule metabolites. Metabolomics represents a promising technique for mechanistic studies and drug screening, and metabonomics, or quantitative metabolomics, has been increasingly applied to the study of hypoxic diseases and their pathogenesis, as well as to pharmacodynamics at high altitudes. In this article, we review the recent literature on the pathogenesis of altitude hypoxia and the clinical and preclinical metabonomics of drug interventions. Endogenous metabolites and metabolic pathways change significantly under high-altitude hypoxia. Some drug interventions have also been shown to regulate pathway metabolism, and the problems of applying metabonomics to hypoxic diseases at high altitude and the prospects for its future application are summarized.
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The effects of environmental hypoxia on substrate utilisation during exercise: a meta-analysis.
Griffiths, A, Shannon, OM, Matu, J, King, R, Deighton, K, O'Hara, JP
Journal of the International Society of Sports Nutrition. 2019;(1):10
Abstract
BACKGROUND A better understanding of hypoxia-induced changes in substrate utilisation can facilitate the development of nutritional strategies for mountaineers, military personnel and athletes during exposure to altitude. However, reported metabolic responses are currently divergent. As such, this systematic review and meta-analysis aims to determine the changes in substrate utilisation during exercise in hypoxia compared with normoxia and identify study characteristics responsible for the heterogeneity in findings. METHODS A total of six databases (PubMed, the Cochrane Library, MEDLINE, SPORTDiscus, PsychINFO, and CINAHL via EBSCOhost) were searched for published original studies, conference proceedings, abstracts, dissertations and theses. Studies were included if they evaluated respiratory exchange ratio (RER) and/or carbohydrate or fat oxidation during steady state exercise matched for relative intensities in normoxia and hypoxia (normobaric or hypobaric). A random-effects meta-analysis was performed on outcome variables. Meta-regression analysis was performed to investigate potential sources of heterogeneity. RESULTS In total, 18 studies were included in the meta-analysis. There was no significant change in RER during exercise matched for relative exercise intensities in hypoxia, compared with normoxia (mean difference: 0.01, 95% CI: -0.02 to 0.05; n = 31, p = 0.45). Meta-regression analysis suggests that consumption of a pre-exercise meal (p < 0.01) and a higher exercise intensity (p = 0.04) when exposed to hypoxia may increase carbohydrate oxidation compared with normoxia. CONCLUSIONS Exposure to hypoxia did not induce a consistent change in the relative contribution of carbohydrate or fat to the total energy yield during exercise matched for relative intensities, compared with normoxia. The direction of these responses appears to be mediated by the consumption of a pre-exercise meal and exercise intensity.
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Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease.
Mirtschink, P, Jang, C, Arany, Z, Krek, W
European heart journal. 2018;(26):2497-2505
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Abstract
Despite strong indications that increased consumption of added sugars correlates with greater risks of developing cardiometabolic syndrome (CMS) and cardiovascular disease (CVD), independent of the caloric intake, the worldwide sugar consumption remains high. In considering the negative health impact of overconsumption of dietary sugars, increased attention is recently being given to the role of the fructose component of high-sugar foods in driving CMS. The primary organs capable of metabolizing fructose include liver, small intestine, and kidneys. In these organs, fructose metabolism is initiated by ketohexokinase (KHK) isoform C of the central fructose-metabolizing enzyme KHK. Emerging data suggest that this tissue restriction of fructose metabolism can be rescinded in oxygen-deprived environments. In this review, we highlight recent progress in understanding how fructose metabolism contributes to the development of major systemic pathologies that cooperatively promote CMS and CVD, reference recent insights into microenvironmental control of fructose metabolism under stress conditions and discuss how this understanding is shaping preventive actions and therapeutic approaches.
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The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation.
Yeo, CD, Kang, N, Choi, SY, Kim, BN, Park, CK, Kim, JW, Kim, YK, Kim, SJ
The Korean journal of internal medicine. 2017;(4):589-599
Abstract
A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors (HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through HIF-1α and HIF-2α. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.
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Hypoxia imaging and radiotherapy: bridging the resolution gap.
Grimes, DR, Warren, DR, Warren, S
The British journal of radiology. 2017;(1076):20160939
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Abstract
Oxygen distribution is a major determinant of treatment success in radiotherapy, with well-oxygenated tumour regions responding by up to a factor of three relative to anoxic volumes. Conversely, tumour hypoxia is associated with treatment resistance and negative prognosis. Tumour oxygenation is highly heterogeneous and difficult to measure directly. The recent advent of functional hypoxia imaging modalities such as fluorine-18 fluoromisonidazole positron emission tomography have shown promise in non-invasively determining regions of low oxygen tension. This raises the prospect of selectively increasing dose to hypoxic subvolumes, a concept known as dose painting. Yet while this is a promising approach, oxygen-mediated radioresistance is inherently a multiscale problem, and there are still a number of substantial challenges that must be overcome if hypoxia dose painting is to be successfully implemented. Current imaging modalities are limited by the physics of such systems to have resolutions in the millimetre regime, whereas oxygen distribution varies over a micron scale, and treatment delivery is typically modulated on a centimetre scale. In this review, we examine the mechanistic basis and implications of the radiobiological oxygen effect, the factors influencing microscopic heterogeneity in tumour oxygenation and the consequent challenges in the interpretation of clinical hypoxia imaging (in particular fluorine-18 fluoromisonidazole positron emission tomography). We also discuss dose-painting approaches and outline challenges that must be addressed to improve this treatment paradigm.