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1.
Autologous fat transplantation alters gene expression patterns related to inflammation and hypoxia in the irradiated human breast.
Lindegren, A, Schultz, I, Sinha, I, Cheung, L, Khan, AA, Tekle, M, Wickman, M, Halle, M
The British journal of surgery. 2019;(5):563-573
Abstract
BACKGROUND Radiation-induced fibrosis, an adverse effect of breast cancer treatment, is associated with functional and cosmetic impairment as well as surgical complications. Clinical reports suggest improvement following autologous fat transplantation, but the mechanisms underlying this effect are unknown. A global gene expression analysis was undertaken to identify genetic pathways dysregulated by radiation and evaluate the impact of autologous fat transplantation on gene expression. METHODS Adipose tissue biopsies were taken synchronously from irradiated and contralateral non-irradiated breasts, before and 1 year after autologous fat transplantation. Whole-genome gene expression analyses were performed, and Hallmark gene set analysis used to explore the effect of radiotherapy and autologous fat transplantation on gene expression. RESULTS Forty microarrays were analysed, using bilateral biopsies taken from ten patients before and after autologous fat transplantation. Forty-five pathways were identified among the 3000 most dysregulated transcripts after radiotherapy in irradiated compared with non-irradiated breast (P ≤ 0·023; false discovery rate (FDR) no higher than 0·026). After autologous fat transplantation, 575 of the 3000 genes were again altered. Thirteen pathways (P ≤ 0·013; FDR 0·050 or less) were identified; the top two canonical pathways were interferon-γ response and hypoxia. Correlative immunohistochemistry showed increased macrophage recruitment in irradiated tissues. CONCLUSION The present findings contribute to understanding of how autologous fat transplantation can ameliorate radiation-induced fibrosis. This further supports the use of autologous fat transplantation in the treatment of radiation-induced fibrosis. Surgical relevance Clinical studies have indicated that autologous fat transplantation (AFT) stimulates regression of chronic inflammation and fibrosis caused by radiotherapy in skin and subcutaneous fat. However, there is a paucity of biological evidence and the underlying processes are poorly understood. Human data are scarce, whereas experimental studies have focused mainly either on the effect of irradiation or AFT alone. The present results indicate that radiotherapy causes dysregulated gene expression in fibrosis-related pathways in adipose tissues in humans. They also show that AFT can cause a reversal of this, with several dysregulated genes returning to nearly normal expression levels. The study provides biological evidence for the impact of AFT on radiation-induced dysregulated gene expression in humans. It supports the use of AFT in the treatment of radiation-induced fibrosis, associated with severe morbidity and surgical challenges.
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2.
Chronic high-dose beetroot juice supplementation improves time trial performance of well-trained cyclists in normoxia and hypoxia.
Rokkedal-Lausch, T, Franch, J, Poulsen, MK, Thomsen, LP, Weitzberg, E, Kamavuako, EN, Karbing, DS, Larsen, RG
Nitric oxide : biology and chemistry. 2019;:44-52
Abstract
Dietary nitrate (NO3-) supplementation via beetroot juice (BR) is known to improve endurance performance in untrained and moderately trained individuals. However, conflicting results exist in well-trained individuals. Evidence suggests that the effects of NO3- are augmented during conditions of reduced oxygen availability (e.g., hypoxia), thereby increasing the probability of performance improvements for well-trained athletes in hypoxia vs. normoxia. This randomized, double-blinded, counterbalanced-crossover study examined the effects of 7 days of BR supplementation with 12.4 mmol NO3- per day on 10-km cycling time trial (TT) performance in 12 well-trained cyclists in normoxia (N) and normobaric hypoxia (H). Linear mixed models for repeated measures revealed increases in plasma NO3- and NO2- after supplementation with BR (both p < 0.001). Further, TT performance increased with BR supplementation (∼1.6%, p < 0.05), with no difference between normoxia and hypoxia (p = 0.92). For respiratory variables there were significant effects of supplementation on VO2 (p < 0.05) and VE (p < 0.05) such that average VO2 and VE during the TT increased with BR, with no difference between normoxia and hypoxia (p ≥ 0.86). We found no effect of supplementation on heart rate, oxygen saturation or muscle oxygenation during the TT. Our results provide new evidence that chronic high-dose NO3- supplementation improves cycling performance of well-trained cyclists in both normoxia and hypoxia.
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3.
[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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4.
Appetite Regulations After Sprint Exercise Under Hypoxic Condition in Female Athletes.
Kojima, C, Kasai, N, Ishibashi, A, Murakami, Y, Ebi, K, Goto, K
Journal of strength and conditioning research. 2019;(7):1773-1780
Abstract
Kojima, C, Kasai, N, Ishibashi, A, Murakami, Y, Ebi, K, and Goto, K. Appetite regulations after sprint exercise under hypoxic condition in female athletes. J Strength Cond Res 33(7): 1773-1780, 2019-The present study determined changes in appetite-regulating hormones and energy intake after high-intensity interval exercise (HIIT) under hypoxic conditions (HYP) in trained female athletes. Fifteen female athletes completed 3 trials on different days of either HIIT under HYP, HIIT under normoxic conditions (NOR), or rest in normoxia (CON). Exercise trials consisted of 2 successive sets of 8 repeated bouts of a 6-second maximal sprint separated by a 30-second rest. Blood samples were obtained to measure plasma acylated ghrelin, glucagon-like peptide-1 (GLP-1), and metabolite concentrations. Energy intake during an ad libitum buffet meal test was evaluated 30 minutes after exercise or rest. Plasma acylated ghrelin concentrations decreased significantly after exercise (p ≤ 0.001), but no difference was observed between the HYP and NOR. Plasma GLP-1 concentrations did not differ after exercise, with no difference between the HYP and NOR. Although absolute energy intake in the HYP (634 ± 67 kcal) and NOR (597 ± 63 kcal) was significantly lower than that in the CON (756 ± 63 kcal, p = 0.006), no difference was observed between the HYP and NOR. These results show that HIIT under hypoxic and NOR lowered plasma acylated ghrelin concentrations and energy intake.
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5.
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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6.
Investigating Effects of Cold Water Hand Immersion on Selective Attention in Normobaric Hypoxia.
Gerhart, HD, Seo, Y, Kim, JH, Followay, B, Vaughan, J, Quinn, T, Gunstad, J, Glickman, EL
International journal of environmental research and public health. 2019;(16)
Abstract
This study investigated the effect of cold-water hand immersion on selective attention as measured by the Stroop Color Word Test in nomorbaric normoxia and hypoxia. Ten healthy men rested for 60 min, after which they immersed their non-dominant hand into 5 °C water for 15 min. The interference score of the Stroop Color Word Test and thermal sensation were measured at baseline in the final 5 min of resting and in the final 5 min of cold water hand immersion. The interference score was not influenced by hypoxia but was found to be significantly improved compared to resting in both conditions during cold water hand immersion. Selective attention improved during 15 min of cold-water hand immersion, with increased thermal sensations rated as "very cool" of the immersed arm. Cold-water hand immersion may be helpful in improving cognitive function in normoxia and normobaric hypoxia.
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7.
Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans.
Dahl, RH, Berg, RMG, Taudorf, S, Bailey, DM, Lundby, C, Christensen, M, Larsen, FS, Møller, K
Scandinavian journal of clinical and laboratory investigation. 2019;(8):595-600
Abstract
Hypoxaemia is present in many critically ill patients, and may contribute to encephalopathy. Changes in the passage of large neutral amino acids (LNAAs) across the blood-brain barrier (BBB) with an increased cerebral influx of aromatic amino acids into the brain may concurrently be present and also contribute to encephalopathy, but it has not been established whether hypoxaemia per se may trigger such changes. We measured cerebral blood flow (CBF) in 11 healthy men using the Kety-Schmidt technique and obtained paired arterial and jugular-venous blood samples for the determination of LNAAs by high performance liquid chromatography at baseline and after 9 hours of poikilocapnic normobaric hypoxia (12% O2). Transcerebral net exchange was determined by the Fick principle, and transport of LNAAs across the BBB was determined mathematically. Hypoxia increased both the systemic and corresponding cerebral delivery of the aromatic amino acid phenylalanine, and the branched-chain amino acids leucine and isoleucine. Despite this, the transcerebral net exchange values and mathematically derived brain extracellular concentrations for all LNAAs were unaffected. In conclusion, the observed changes in circulating LNAAs triggered by hypoxaemia do not affect the transcerebral exchange kinetics of LNAAs to such an extent that their brain extracellular concentrations are affected.
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8.
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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9.
Iron Prevents Hypoxia-Associated Inflammation Through the Regulation of Nuclear Factor-κB in the Intestinal Epithelium.
Simmen, S, Cosin-Roger, J, Melhem, H, Maliachovas, N, Maane, M, Baebler, K, Weder, B, Maeyashiki, C, Spanaus, K, Scharl, M, et al
Cellular and molecular gastroenterology and hepatology. 2019;(2):339-355
Abstract
BACKGROUND & AIMS Hypoxia-associated pathways influence the development of inflammatory bowel disease. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are regulated by iron-dependent hydroxylases. Signals reflecting oxygen tension and iron levels in enterocytes regulate iron metabolism. Conversely, iron availability modulates responses to hypoxia. In the present study we sought to elucidate how iron influences the responses to hypoxia in the intestinal epithelium. METHODS Human subjects were exposed to hypoxia, and colonic biopsy specimens and serum samples were collected. HT-29, Caco-2, and T84 cells were subjected to normoxia or hypoxia in the presence of iron or the iron chelator deferoxamine. Changes in inflammatory gene expression and signaling were assessed by quantitative polymerase chain reaction and Western blot. Chromatin immunoprecipitation was performed using antibodies against nuclear factor (NF)-κB and primers for the promoter of tumor necrosis factor (TNF) and interleukin (IL)1β. RESULTS Human subjects presented reduced levels of ferritin in the intestinal epithelium after hypoxia. Hypoxia reduced iron deprivation-associated TNF and IL1β expression in HT-29 cells through the induction of autophagy. Contrarily, hypoxia triggered TNF and IL1β expression, and NF-κB activation in Caco-2 and T84 cells. Iron blocked autophagy in Caco-2 cells, while reducing hypoxia-associated TNF and IL1β expression through the inhibition of NF-κB binding to the promoter of TNF and IL1β. CONCLUSIONS Hypoxia promotes iron mobilization from the intestinal epithelium. Hypoxia-associated autophagy reduces inflammatory processes in HT-29 cells. In Caco-2 cells, iron uptake is essential to counteract hypoxia-induced inflammation. Iron mobilization into enterocytes may be a vital protective mechanism in the hypoxic inflamed mucosa.
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10.
Hypoxia attenuates inflammation-induced hepcidin synthesis during experimental human endotoxemia.
Kiers, D, van Eijk, LT, van der Hoeven, JG, Swinkels, DW, Pickkers, P, Kox, M
Haematologica. 2019;(6):e230-e232