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1.
[Role of Ca2+ in hypoxic pulmonary vasoconstriction].
Wei, G, Cheng, Y, Huang, Y, He, Q
Zhonghua wei zhong bing ji jiu yi xue. 2019;(5):647-649
Abstract
In acute hypoxia, pulmonary vascular will contract and divert blood to better ventilated area to optimize ventilation/perfusion matching, which is known as hypoxic pulmonary vasoconstriction (HPV). In chronic hypoxia, irreversible pulmonary vascular remodeling can be induced, characterized by pulmonary artery middle smooth muscle cells and the outer fiber cell hyperplasia in luminal stenosis and pulmonary artery hypertension (PAH) eventually. Furthermore, PAH can cause increased ventricular afterload, and right heart failure in severe cases. Pulmonary artery smooth muscle cell (PASMC) elevated Ca2+ concentration is one of the most important factors of its contractions, proliferation and migration. Recent studies on Ca2+ promoting in HPV were summarized in order to provide evidence for clinical prevention of hypoxia and therapeutic PAH.
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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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3.
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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4.
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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5.
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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[Is Oxygen Deficiency Always Harmful?].
Schläpfer, M
Praxis. 2018;(21):1155-1159
Abstract
Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.
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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.
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Muscle Protein Turnover and the Molecular Regulation of Muscle Mass during Hypoxia.
Pasiakos, SM, Berryman, CE, Carrigan, CT, Young, AJ, Carbone, JW
Medicine and science in sports and exercise. 2017;(7):1340-1350
Abstract
: Effects of environmental hypoxia on fat-free mass are well studied. Negative energy balance, increased nitrogen excretion, and fat-free mass loss are commonly observed in lowlanders sojourning at high altitude. Reductions in fat-free mass can be minimized if energy consumption matches energy expenditure. However, in nonresearch settings, achieving energy balance during high-altitude sojourns is unlikely, and myofibrillar protein mass is usually lost, but the mechanisms accounting for the loss of muscle mass are not clear. At sea level, negative energy balance reduces basal and blunts postprandial muscle protein synthesis, with no relevant change in muscle protein breakdown. Downregulations in muscle protein synthesis and loss of fat-free mass during energy deficit at sea level are largely overcome by consuming at least twice the recommended dietary allowance for protein. Hypoxia may increase or not affect resting muscle protein synthesis, blunt postexercise muscle protein synthesis, and markedly increase proteolysis independent of energy status. Hypoxia-induced mTORC1 dysregulation and an upregulation in calpain- and ubiquitin proteasome-mediated proteolysis may drive catabolism in lowlanders sojourning at high altitude. However, the combined effects of energy deficit, exercise, and dietary protein manipulations on the regulation of muscle protein turnover have never been studied at high altitude. This article reviews the available literature related to the effects of high altitude on fat-free mass, highlighting contemporary studies that assessed the influence of altitude exposure (or hypoxia) on muscle protein turnover and intramuscular regulation of muscle mass. Knowledge gaps are addressed, and studies to identify effective and feasible countermeasures to hypoxia-induced muscle loss are discussed.
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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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10.
Function and Dysfunction of Adipose Tissue.
Matafome, P, Seiça, R
Advances in neurobiology. 2017;:3-31
Abstract
Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.