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The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the ‘Warburg reprogramming’ of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of ‘anti-Warburg’ effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted ‘anti-Warburg’ measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted ‘anti-Warburg’ measures in the context of predictive, preventive and personalised medicine.

Purpose: Repeated-sprint training (RS) is commonly conducted in normoxia, but its completion with localized (blood-flow restriction [BFR]) or systemic hypoxia has been proven effective for performance enhancement. Yet, few studies have applied these types of RS sessions in racket sports. The authors aimed to determine the acute responses to these types of training in elite badminton players. Methods: Eight male elite badminton players participated in this randomized crossover study. They performed 3 on-court RS sessions, each consisting of 3 sets of 10 repetitions of 10-s badminton-specific movements in normoxia (RSN), systemic normobaric hypoxia (RSH, FiO2 = 14%), or with BFR (RS-BFR, 40% arterial occlusion pressure). Performance, perceptual (ie, rating of perceived exertion), and physiological (ie, pulse saturation, muscle oxygenation, blood lactate, creatine kinase, heart-rate variability) responses were measured after each set and up to 48 h postsession. Results: RS-BFR induced a greater performance impairment (lower distance and accelerations) and a higher local perceived exertion in the legs than RSN and RSH (P P P Conclusions: RS-BFR—and, to a lower extent, RSH—resulted in impaired performance and a higher perceived strain than RSN. However, these 2 hypoxic methods do not seem to induce a long-lasting (post 24–48 h) physiological stress in elite badminton players.

This study quantified performance, physiological, and perceptual responses during resistance exercise to task failure with blood flow restriction (BFR), in systemic hypoxia, and with these stimuli combined.Fourteen young men were tested for 1-repetition maximum (1RM) in the barbell biceps curl and lying triceps extension exercises. On separate visits, subjects performed exercise trials (4 sets to failure at 70% 1RM with 90 s between sets) in six separate randomized conditions, i.e., in normoxia or hypoxia (fraction of inspired oxygen = 20.9% and 12.9%, respectively) combined with three different levels of BFR (0%, 45%, or 60% of resting arterial occlusion pressure). Muscle activation and oxygenation were monitored via surface electromyography and near-infrared spectroscopy, respectively. Arterial oxygen saturation, heart rate, and perceptual responses were assessed following each set.Compared to set 1, the number of repetitions before failure decreased in sets 2, 3, and 4 for both exercises (all P 0.001), independently of the condition (P 0.065). Arterial oxygen saturation was lower with systemic hypoxia (P 0.001), but not BFR, while heart rate did not differ between conditions (P 0.341). Muscle oxygenation and activation during exercise trials remained unaffected by the different conditions (all P ≥ 0.206). A significant main effect of time, but not condition, was observed for overall perceived discomfort, difficulty breathing, and limb discomfort (all P 0.001).Local and systemic hypoxic stimuli, or a combination of both, did not modify the fatigue-induced change in performance, trends of muscle activation or oxygenation, nor exercise-related sensations during a multi-set resistance exercise to task failure.

Induction of hypothermia and consequent hypometabolism by pharmacological downmodulation of the internal thermostat could be protective in various medical situations such as ischemia/reperfusion. Systemic hypoxia is a trigger of thermostat downregulation in some mammals, which is sensed though carotid chemoreceptors (carotid bodies, CBs). Using non-invasive thermographic imaging in mice, we demonstrated that surgical bilateral CB denervation does not hamper hypoxia-induced hypothermia. However, the recovery from a protective and reversible hypothermic state after restoration to normoxic conditions was impaired in CB-resected mice versus control animals. Therefore, the carotid chemoreceptors play an important role in the central regulation of hypoxia-driven hypothermia in mice, but only in the rewarming phase.

Purpose: The authors compared the effects of active preconditioning with local and systemic hypoxia during submaximal cycling. Methods: On separate visits, 14 active participants completed 4 trials. Each visit was composed of 1 preconditioning phase followed, after 40 minutes of rest, by 3 × 6-minute cycling bouts (intensity = 85% of critical power; rest = 6 min). The preconditioning phase consisted of 4 × 5-minute cycling bouts at 1.5 W·kg−1 (rest = 5 min) in 4 conditions: control (no occlusion and normoxia), blood flow restriction (60% of total occlusion), HYP (systemic hypoxia; inspired fraction of oxygen = 13.6%), and blood flow restriction + HYP (local and systemic hypoxia combined). Results: During the preconditioning phase, there were main effects of both systemic (all P P ≤ .001) on heart rate, arterial oxygen saturation, leg discomfort, difficulty of breathing, and blood lactate concentration. Cardiorespiratory variables, gross efficiency, energy cost, and energy expenditure during the last minute of 6-minute cycling bouts did not differ between conditions (all P > .105). Conclusion: Local and systemic hypoxic stimuli, or a combination of both, during active preconditioning did not improve physiological responses such as cycling efficiency during subsequent submaximal cycling.

This chapter reviews the effects of systemic hypoxia and blood flow restriction on cellular adaptations to training. Strategies for implementing hypoxic training and the efficacy of performing different exercise modalities under hypoxic conditions is discussed. Along with differentiating systemic hypoxia from blood flow restricted exercise, this chapter provides an overview on how to safely administer blood flow restricted exercise, as well as detailing some of the adaptations that occur in response to blood flow restriction administered at res, and in combination with different exercise modalities. Current limitations and future directions for both systemic hypoxia and blood flow restricted exercise are also discussed.

Experimental hypoxia has been used for decades to examine the adaptive response to low-oxygen environments. Various models have been studied, including flies, worms, fish, rodents, and humans. Our lab has recently used this technology to examine the effect of environmental hypoxia on mammalian heart regeneration. In this chapter, we describe studies of systemic hypoxia in mice. We found that systemic hypoxia can blunt oxidative DNA damage and induce cardiomyocyte proliferation. While our primary interests are focused on cardiovascular research, these hypoxia protocols are applicable to any other organ system.

International audience; With minimal costs and travel constraints for athletes, the "living low-training high" (LLTH) approach is becoming an important intervention for modern sport. The popularity of the LLTH model of altitude training is also associated with the fact that it only causes a slight disturbance to athletes' usual daily routine, allowing them to maintain their regular lifestyle in their home environment. In this perspective article, we discuss the evolving boundaries of the LLTH paradigm and its practical applications for athletes. Passive modalities include intermittent hypoxic exposure at rest (IHE) and Ischemic preconditioning (IPC). Active modalities use either local [blood flow restricted (BFR) exercise] and/or systemic hypoxia [continuous low-intensity training in hypoxia (CHT), interval hypoxic training (IHT), repeated-sprint training in hypoxia (RSH), sprint interval training in hypoxia (SIH) and resistance training in hypoxia (RTH)]. A combination of hypoxic methods targeting different attributes also represents an attractive solution. In conclusion, a growing number of LLTH altitude training methods exists that include the application of systemic and local hypoxia stimuli, or a combination of both, for performance enhancement in many disciplines.

Aim: Deviation of the nasal septum, which can cause upper respiratory tract obstruction and systemic hypoxia, may also affect the eye. The aim of this study was to detect changes in posterior segment parameters of the eye in patients with nasal septal deviation. Material and Methods: The study included 50 patients with nasal septal deviation, and a control group of 30 healthy subjects with no nasal septal deviation. Choroidal thickness, central macular thickness and retinal nerve fiber layer thickness were measured with Optical Coherence Tomography. Results: Choroidal thickness was significantly lower in patients with severe nasal septal deviation compared to the control group. (p=0.001) There is no statistically significant change in other measurements. Conclusion: The study results suggest that marked nasal septal deviation may lead to significant hypoxia and sympathetic activation, resulting in deterioration of the choroidal blood flow and consequent choroidal thickening.

N2O, or laughing gas, is generally used for anesthesia, especially in stomatology and pediatrics but is also commonly used recreationally. Cognitive dysfunction induced by the recreational use of N2O is rare. Here, we present the case of an 18-year-old female with a history of having used N2O recreationally for 5 months who suffered from encephalatrophy and severe cognitive dysfunction. All of the symptoms gradually subsided with ~20 days of treatment by hyperbaric oxygenation. We hypothesize that the long-term use of N2O may have induced a chronic state of systemic hypoxia that further induced cerebral atrophy with impaired cognitive function. Hyperbaric oxygen therapy (HBOT) is reported here for the first time as an important therapeutic element for treating N2O toxicity due to recreational use.

Breast cancer (BC) epidemic in the twenty-first century is characterised by around half a million deaths and 1.7 million new cases registered annually worldwide. Metastatic disease is the major cause of death in BC patient cohorts. Current statistics are much alarming from the viewpoint of the early mortality amongst BC patients with de novo metastatic disease. A new paradigm of so-called “pre-metastatic niches” may sufficiently promote our knowledge regarding potential pathomechanisms, individual predisposition and prognosis in development and progression of the metastatic disease. However, the crucial question remains unaddressed, whether hypoxic pre-metastatic niches in BC are created by or prior to the tumour onset. So far, the current interpretation of the “Seed and Soil” theory of metastasis proposing that the pre-metastatic niches are formed by primary tumours which “induce and guide” the process is incomplete, since it does not provide satisfactory explanations towards several facts overviewed in the article. The overall results of this study clearly support the working hypothesis presented by the authors proposing that the epi/genetic predisposition of individuals at risk to form the systemic hypoxic pre-metastatic niches can be established a long time before breast malignancy is clinically manifested. “Flammer Syndrome” (FS) phenotype may strongly contribute to particularly poor outcomes of metastatic breast cancer. Significance and relevance of individual FS symptoms for breast cancer metastatic disease are discussed in extenso.

Systemic hypoxia is a physiological and pathophysiological stress that activates the sympathoadrenal system and, in young adults, leads to peripheral vasodilation. We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia is impaired in older healthy adults and that this age-associated impairment is due to attenuated β-adrenergic mediated vasodilation and elevated α-adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound), and vascular conductance (FVC) was calculated in 12 young (24 ± 1 yr) and 10 older (63 ± 2 yr) adults to determine the local dilatory responses to graded hypoxia (90, 85, and 80% O2 saturations) in control conditions, following local intra-arterial blockade of β-receptors (propranolol), and combined blockade of α- and β-receptors (phentolamine + propranolol). Under control conditions, older adults exhibited impaired vasodilation to hypoxia compared with young participants at all levels of hypoxia (peak ΔFVC at 80% [Formula: see text] = 4 ± 6 vs. 35 ± 8%; P < 0.01). During β-blockade, older adults actively constricted at 85 and 80% [Formula: see text] (peak ΔFVC at 80% [Formula: see text] = −13 ± 6%; P < 0.05 vs. control), whereas the response in the young was not significantly impacted (peak ΔFVC = 28 ± 8%). Combined α- and β-blockade increased the dilatory response to hypoxia in young adults; however, older adults failed to significantly vasodilate (peak ΔFVC at 80% [Formula: see text]= 12 ± 11% vs. 58 ± 11%; P < 0.05). Our findings indicate that peripheral vasodilation to graded systemic hypoxia is significantly impaired in older adults, which cannot be fully explained by altered sympathoadrenal control of vascular tone. Thus, the impairment in hypoxic vasodilation is likely due to attenuated local vasodilatory and/or augmented vasoconstrictor signaling with age. NEW & NOTEWORTHY We found that the lack of peripheral vasodilation during graded systemic hypoxia with aging is not mediated by the sympathoadrenal system, strongly implicating local vascular control mechanisms in this impairment. Understanding these mechanisms may lead to therapeutic advances for improving tissue blood flow and oxygen delivery in aging and disease.

NEW FINDINGS What is the central question of this study? Is an anti-oedematous effect of ghrelin associated with increased expression of tight junction proteins in the hypoxic brain? What is the main finding and its importance? We showed that injection of ghrelin during acute and chronic systemic hypoxia is associated with increased expression of tight junction proteins and protection of the blood-brain barrier. Ghrelin appears to be a new therapeutic strategy for protection of the blood-brain barrier from disruption and prevention of brain oedema in hypoxic conditions. The blood-brain barrier, which serves to protect the homeostasis of the CNS, is formed by tight junction proteins. Several studies have indicated that systemic hypoxia leads to cerebral oedema through disruption of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). According to our previous studies, ghrelin attenuates cerebral oedema in the hypoxic brain. However, the mechanism is not completely understood. The present study was designed to determine the effect of ghrelin on occludin and ZO-1 in the hypoxic brain. Adult male Wistar rats were divided into acute and chronic control, acute or chronic hypoxia, and ghrelin-treated acute or chronic hypoxia groups. Hypoxic groups were kept in a hypoxic chamber (10-11% O2 ) for 2 (acute) or 10 days (chronic). Effects of ghrelin on occludin and ZO-1 protein levels were assessed using Western blotting. Western blot analysis revealed that the protein expression of ZO-1 and occludin decreased significantly in acute and chronic hypoxia. Ghrelin significantly increased ZO-1 protein expression in both acute and chronic hypoxia (P

Why does healthcare of breast cancer (BC) patients, especially in a young population, matter and why are innovative strategies by predictive, preventive, and personalized medicine (PPPM) strongly recommended to replace current reactive medical approach in BC management? Permanent increase in annual numbers of new BC cases with particularly quick growth of premenopausal BC patients, an absence of clearly described risk factors for those patients, as well as established screening tools and programs represent important reasons to focus on BC in young women. Moreover, "young" BC cases are frequently "asymptomatic", difficult to diagnose, and to treat effectively on time. The objective of this article is to update the knowledge on BC in young females, its unique molecular signature, newest concepts in diagnostics and therapy, and to highlight the concepts of predictive, preventive, and personalized medicine with a well-acknowledged potential to advance the overall disease management.

Objective. According to our previous studies, ghrelin protects blood brain barrier (BBB) integrity and it attenuates hypoxia-induced brain edema in the hypoxic conditions. However, the underlying mechanisms remain poorly understood. Several studies suggest a role for matrix metal-loproteinase-9 (MMP9) in the BBB disruption and cerebral edema formation. The present study was conducted to determine the effect of ghrelin on MMP9 protein expression in the model of acute and chronic systemic hypoxia. Methods. Adult male Wistar rats were divided into acute or chronic controls, acute or chronic hypoxia and ghrelin-treated acute or chronic hypoxia groups. The hypoxic groups were kept in the hypoxic chamber (10–11% O2) for two (acute) or ten days (chronic). Effect of ghrelin on MMP9 protein expression was assessed using immunoblotting. Results. Our results showed that acute and chronic systemic hypoxia increased the MMP9 protein expression in the brain (p Conclusion. Our results demonstrate that the neuroprotective effects of ghrelin may be mediated, in part, by decreasing in MMP9 production in the hypoxic brain.

In aquatic toxicology, the functional anatomy of fishes and the presence of organ pathologies has informed us about the modes of action of toxic substances. However, a similar understanding has yet to emerge for engineered nanomaterials (ENMs). This chapter uses a target organ approach to identify the pathologies that have been associated with the body systems of fish. The focus is exclusively on in vivo exposures and the pathologies that develop in vivo. Exposure to high concentrations of ENMs can compromise the integrity of external barriers such as the gut and the gills of fish. All of the major body systems and most of internal organs show evidence of pathology from in vivo exposures. Injuries include fatty change in the liver, the presence of necrotic cells in the renal tubules, melanomacrophage deposits in the spleen and degeneration of the skeletal muscle fibres. There is also evidence of indirect brain pathology, most likely arising from vascular injury and/or systemic hypoxia. Unequivocal demonstration of brain pathology from ENMs inside the matter of the brain is yet to be demonstrated in vivo. However, some effects on sense organs, and changes in behaviour due to altered sensory perception have been observed. Only a few seemingly nano-specific pathologies have been found. Most pathologies are also known for traditional chemicals, although the aetiology is often different for the nano form. There are many data gaps, with the information limited to a few species of fish and mostly pristine ENMs.

Significant deficits in breast cancer management led to the epidemic of the pathology in the early twenty-first century. Therefore, it is an emergency now to revise the persisting traditional approaches in BC management as well as to broaden our vision in many aspects regarding the BC aetiology and multi-factorial risks creating new concepts for effective screening programmes, innovative predictive, preventive and prognostic approaches tailored to the person.

Aim. To study the relation of the pattern of erythrocyte sphericity value changes and the levels of structural and functional proteins of erythrocyte membrane in patients with arterial hypertension (AH). Material and methods. Totally, 51 patient participated with AH of 1 and 2 grade (mean age 42±1,5 y.), in whom we assessed sphericity of erythrocytes (SE) and performed quantitative evaluation of 10 membrane proteins of erythrocytes. Analysis of the acquired data was done via non- and parametrical statistics methods. Results. All AH patients were selected to a group with “normocytosis” (SE ≥3,4 U) and “spherocytosis” (SE

In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite significant reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that 1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; 2) PGs do not normally contribute to vascular tone during hypoxia, however, they do affect vascular tone when NO is inhibited; 3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and 4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, skeletal muscle blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts augmented vasodilation and hyperemia compared with control (normoxic) conditions by ∼50%; however, in contrast to hypoxia alone, the response is not abolished, suggesting that other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release, or nitrite reduction to NO, or both likely play a role in regulating this response.

Kosaku, Kazuhiro, Tomonori Harada, Toyoharu Jike, Isao Tsuboi, and Shin Aizawa. Long-term hypoxic tolerance in murine cornea. High Alt Med Biol 19:35-41, 2018.The cornea is believed to be an exceedingly sensitive organ to decreases in atmospheric oxygen concentrations. Previous corneal studies have shown the hypoxic tolerance of the cornea during short-term and local hypoxic exposure. This study investigated the tolerance of the cornea during long-term and systemic hypoxia.Mice were bred under normobaric normoxia or hypoxia (10% oxygen concentration) conditions for 140 days. The layer structure, surface microvilli, and glycogen granules in the corneal epithelium were examined on day 2 and on day 140. The layer and surface structures of the corneal epithelium were normally maintained during the long-term hypoxia. Hypoxic stress caused a decrease in the glycogen granules in the corneal epithelial cells.Maintenance of normal structures during long-term hypoxia suggests that the cornea has a high tolerance for hypoxic stress. The quantity of glycogen in corneal epithelial cells is considered an index of corneal hypoxia resistance.

The steenbok (Raphicerus campestris) is a small antelope of the family Bovidae native to the African continent. Urolithiasis, the formation of urinary calculi in the urinary tract, can be caused by a variety of factors such as diet, dehydration, infection and anatomical predisposition. Urolithiasis, with uroliths identified as magnesium calcium phosphate carbonate in composition, was diagnosed in a hand-reared 5-month-old steenbok. Perineal urethrostomy was performed as a component of the broad treatment regime that included fluid therapy, antibiotic and anti-inflammatory treatment. However, the animal died 4 days later as a result of systemic hypoxia and energy depletion because of stress and cachexia. The challenges of post-surgical treatment, the importance of positive energy balance in small ruminants under stressful circumstances, as well as the role of diet of hand-reared antelope in predisposition to urolith formation are highlighted.

Dipeptidyl peptidase 4 (DPP4) is a transmembrane glycoprotein involved in protein degradation. Due to its action on incretins, which increase insulin secretion, DPP4 is considered a therapeutic target for type 2 diabetes. Here we have studied the role of single and combined effects of hypoxia and inactivity on the expression of DPP4 in human adipose tissue of 12 adult normal-weight males. Fat biopsies were obtained at baseline and after each of three experimental campaigns. The results revealed that in isolated human preadipocytes the expression of DPP4 was significantly increased by exposure of participants to hypoxia. Physical inactivity per se had no apparent effect on the DPP4 expression. It is concluded that DPP4 may be a marker to monitor indirectly tissue hypoxia, as occurs in obese subjects.

Breast cancer (BC) epidemic is recognised now worldwide as the reality of the early twenty-first century. Increasing trends in the postmenopausal BC prevalence, even for the European countries earlier demonstrating relatively stable incidence rates of the disease, are highly alarming for the healthcare givers. This new actuality requires a substantial revision of the paradigm currently applied to the BC management and creation of highly innovative concepts. Current multi-centred study highlights new complex mechanisms of the development and progression of the postmenopausal BC. Innovative concepts are presented which argue for more effective predictive and preventive approaches well justified in view of the clusters of the symptoms analysed here and demonstrated as highly prevalent in the postmenopausal breast cancer versus BC-free individuals. Another conceptual novelty presented here is a new interpretation of the “Seed and Soil” theory of metastasis in BC. According to the new concept, the “pre-metastatic niches” (“Soil”) are created by a systemic hypoxia a long time before the breast malignancy is clinically manifested.

An epidemic scale of the breast cancer (BC) prevalence is actually recognised as the reality of the early twenty-first century. Particularly alarming is that the sporadic BC (about 90% of all patients) creates currently unpredictable subpopulations in terms of disease predisposition, development and progression. Despite broad discussions run since years in BC area, no any plausible approach has been suggested so far to get the overall situation better controlled in the populations. Here, we present highly innovative concepts considering investigation of specific syndromes and symptoms underestimated till now in relationship with BC predisposition and development. Consequently, the purpose of our pilot project was to evaluate the prevalence of Flammer Syndrome (FS) in BC patient cohort. The results achieved here support the main hypothesis of the project clearly demonstrating the tendency of BC patients to the increased prevalence of FS symptoms compared to the disease-free individuals. Our study strongly indicates the relevance of FS symptoms for BC pathology such as feeling inadequately cold, deficient thermoregulation, altered sensitivity to different stimuli, potential dehydration, altered sleep patterns, tendency towards headache, migraine attacks and dizziness. Moreover, the symptoms’ appearance is specifically linked to the individual BC subtypes. Potential mechanisms interconnecting FS with BC pathology are discussed.

Staphylococcal infection and neutrophilic inflammation can act in concert to establish a profoundly hypoxic environment. In this review we summarise how neutrophils and Staphylococcus aureus are adapted to function under hypoxic conditions, with a particular focus on the impaired ability of hypoxic neutrophils to effect Staphylococcus aureus killing.

Profound systemic hypoxemia in a neonate, unresponsive to supplemental oxygen, is usually secondary to structural heart disease or persistent pulmonary hypertension (PPHN). Pulmonary arteriovenous malformations (AVMs) and direct communications from the pulmonary artery (PA) to the atria are other

Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signalling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavourable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology.

Mast cells are immune cells of the myeloid lineage and are present in connective tissues throughout the body. The activation and degranulation of mast cells significantly modulates many aspects of physiological and pathological conditions in various settings. With respect to normal physiological functions, mast cells are known to regulate vasodilation, vascular homeostasis, innate and adaptive immune responses, angiogenesis, and venom detoxification. On the other hand, mast cells have also been implicated in the pathophysiology of many diseases, including allergy, asthma, anaphylaxis, gastrointestinal disorders, many types of malignancies, and cardiovascular diseases. This review summarizes the current understanding of the role of mast cells in many pathophysiological conditions.

Hypoxia and light illumination can both decrease oxygen consumption in the photoreceptor layers. The purpose of the present study was to investigate whether the mutual effects of hypoxia and intense illumination to the photoreceptors are additive. The a-wave of flash electroretinogram (fERG) was recorded to indirectly measure the photoreceptors function under given conditions. Six normal healthy subjects, mean age 34.0 ± 3.8 years, all of whom had high-altitude (3,000 m) mountain hiking experience, were recruited for the study. Flash a-wave electroretinography was examined under four conditions: (1) normal (D/N); (2) systemic hypoxia induced by inhaling a mixture of O(2) and N(2) gases, which caused oxyhemoglobin saturation (SaO(2)) ≈ 80% (D/H); (3) intense light illumination, which resulted in photoreceptor bleaching (B/N); and (4) a combination of conditions b and c (B/H). Thirty light stimuli, each with a 20-ms ON and 1,980-ms OFF cycle, were given and ERG performed to probe the photoreceptor function. The results showed that a-wave at the various conditions did not respond to all stimuli. The average a-wave amplitudes were 91.4 ± 46.5, 22.8 ± 42.5, 15.5 ± 28.9, and 35.2 ± 41.1 μV for D/N, D/H, B/N, and B/H, respectively. Nonparametric Friedman test for a-wave amplitude indicated that significant differences occurred in D/N-D/H, D/N-B/N, D/N-B/H, D/H-B/H, and B/N-B/H (all p values were0.001, but D/H-B/N was 0.264). Thus, systemic hypoxia or strong illumination to the retina can cause an absence of the ERG a-wave or change its response, although individual differences were observed. In this study, systemic hypoxia appeared to reduce photoreceptor bleaching, an interesting finding in itself. The mechanisms underlying the disappearance of the ERG a-wave following hypoxia or intense illumination to the photoreceptors seem to differ.

Heinonen IH, Kemppainen J, Kaskinoro K, Peltonen JE, Borra R, Lindroos M, Oikonen V, Nuutila P, Knuuti J, Boushel R, Kalliokoski KK. Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia. Am J Physiol Regul Integr Comp Physiol 299: R72-R79, 2010. First published April 28, 2010; doi:10.1152/ajpregu.00056.2010.-Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to similar to 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.

Recently, Kon et al. (5) published in this journal an interesting paper entitled “Effects of systemic hypoxia on human muscular adaptations to resistance exercise training “ which determined the effect of 8 weeks of resistance training (5 sets of 10 reps at 70% of 1 RM of free weight bench‐press and bilateral leg‐press using a weight‐stack machine) under hypoxia (HRT, 14.4% O2) or normoxia, on muscle cross‐sectorial area, 1 RM, muscular endurance and markers of mitochondrial biogenesis and angiogenesis. Their conclusion suggested two important findings: (1) an increased muscular endurance and, (2) the promotion of angiogenesis in skeletal muscle in the hypoxic‐trained subjects compared to the normoxic‐trained subjects. However, in our opinion, a number of the comments in the Kon et al. (5) publication need clarification, moreover, the author's conclusions may only partially explain the benefits of resistance training in hypoxia for endurance athletes. In the discussion section, the author's state: “For the first time, we demonstrate a significant resistance‐training‐induced increase in muscular endurance in the …

Hypoxia is an important modulator of endurance exercise‐induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise‐induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross‐sectional area (CSA), one‐repetition maximum (1RM), muscular endurance, and makers of mitochondrial biogenesis and angiogenesis, such as peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), citrate synthase (CS) activity, nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), hypoxia‐inducible factor‐1 (HIF‐1), and capillary‐to‐fiber ratio. Sixteen healthy male subjects were randomly assigned to either a normoxic resistance training group (NRT, n =7) or a hypoxic (14.4% oxygen) resistance training group (HRT, n =9) and performed 8 weeks of resistance training. Blood and muscle biopsy samples were obtained before and after training. After training muscle CSA of the femoral region, 1RM for bench‐press and leg‐press, muscular endurance, and skeletal muscle VEGF protein levels significantly increased in both groups. The increase in muscular endurance was significantly higher in the HRT group. Plasma VEGF concentration and skeletal muscle capillary‐to‐fiber ratio were significantly higher in the HRT group than the NRT group following training. Our results suggest that, in addition to increases in muscle size and strength, HRT may also lead to increased muscular endurance and the promotion of angiogenesis in skeletal muscle., This study investigated the effect of resistance exercise training performed under systemic hypoxia or normoxia on biochemical and molecular muscular adaptations in healthy male subjects. Our findings demonstrate that resistance training under systemic hypoxia led not only muscle hypertrophy, but most interestingly, to a greater increase in muscular endurance. This increase in muscular endurance was potentially caused by the increased angiogenesis as determined by capillary‐to‐fiber ratio.

Background: Although certain studies report high levels of vascular endothelial growth factor (VEGF) in obstructive sleep apnea syndrome (OSAS), the effect of systemic hypoxia on circulating VEGF remains controversial. Objectives: To study the association of serum VEGF and OSAS in a large group of patients. Methods: One hundred patients with OSAS (mean age 58.1 ± 12.4 years, mean body mass index 30.6 ± 5.4 kg/m2) were tested for serum VEGF levels, and the findings were correlated with the severity of OSAS, as determined by the apnea-hypopnea index (AHI) on the basis of polysomnography and background data. Results: The mean AHI was 40.0 ± 21.2 (range 10–106). Mean minimal oxygen saturation was 80.6 ± 11.7% (range 43–98%) and mean time of oxygen saturation under 90% was 50.0 ± 75.0 min (range 0–300 min). The mean VEGF level was 445.2 ± 289.8 pg/ml in the study group (vs. 280 pg/ml reported in normal controls). The mean platelet count was 233.8 ± 64.4 103/ml and the mean VEGF/platelet ratio was 1.95 ± 1.40 pg/106. There was no association of VEGF or VEGF/platelets with the severity of OSAS. However, both factors showed a significant correlation with patient age (r = 0.224, p = 0.01 and r = 0.425, p = 0.01, respectively). Age was the only parameter to significantly predict VEGF and VEGF/platelets on multivariate analysis (R2 = 0.713, p = 0.001 and R2 = 0.844, p = 0.001, respectively). Conclusion: The elevation of serum VEGF in OSAS is not associated with the severity of the disease, but it is associated with patient age. VEGF might be involved in the long-term adaptive mechanism in OSAS, and its age-dependent increase might partly explain the reduced mortality in elderly OSAS patients.

As arterial partial pressure of O2 (PaO2) is reduced during systemic hypoxia, right ventricular (RV) work and myocardial O2 consumption (MV̇o2) increase. Mechanisms responsible for maintaining RV O2 demand/supply balance during hypoxia have not been delineated. To address this problem, right coronary (RC) blood flow and RV O2 extraction were measured in nine conscious, instrumented dogs exposed to normobaric hypoxia. Catheters were implanted in the right ventricle for measuring pressure, in the ascending aorta for measuring arterial pressure and for sampling arterial blood, and in an RC vein. A flow transducer was placed around the RC artery. After recovery from surgery, dogs were exposed to hypoxia in a chamber ventilated with N2, and blood samples and hemodynamic data were collected as chamber O2 was reduced progressively to ∼8%. After control measurements were made, the chamber was opened and the dog was allowed to recover. Nω-nitro-l-arginine (l-NNA) was then administered (35 mg/kg, via RV catheter) to inhibit nitric oxide (NO) production, and the hypoxia protocol was repeated. RC blood flow increased during hypoxia due to coronary vasodilation, because RC conductance increased from 0.65 ± 0.05 to 1.32 ± 0.12 ml·min−1·100 g−1. l-NNA blunted the hypoxia-induced increase in RC conductance. RV O2 extraction remained constant at 64 ± 4% as PaO2 was decreased, but after l-NNA, extraction increased to 70 ± 3% during normoxia and then to 78 ± 3% during hypoxia. RV MV̇o2 increased during hypoxia, but after l-NNA, MV̇o2 was lower at any respective PaO2. The relationship between heart rate times RV systolic pressure (rate-pressure product) and RV MV̇o2 was not altered by l-NNA. To account for l-NNA-mediated decreases in RV MV̇o2, O2 demand/supply variables were plotted as functions of MV̇o2. Slope of the conductance-MV̇o2 relationship was depressed by l-NNA ( P = 0.03), whereas the slope of the extraction-MV̇o2 relationship increased ( P = 0.003). In summary, increases in RV MV̇o2 during hypoxia are met normally by increasing RC blood flow. When NO synthesis is blocked, the large RV O2 extraction reserve is mobilized to maintain RV O2 demand/supply balance. We conclude that NO contributes to RC vasodilation during systemic hypoxia.

Yijiang, Zhou, Zhu Jianhua, and Lin Feili. Acute kidney injury at high altitude. High Alt Med Biol 14:183–185, 2013.—Acute ascent to high altitudes beyond 2400 m (300 feet) can cause acute mountain sickness (AMS) and may develop into life-threatening complications such as high altitude cerebral (HACE) and pulmonary edema (HAPE). We report a case of acute kidney injury (AKI) without other organ involvement in a previously healthy young man after sudden high altitude exposure of up to 5200 m. Acute systemic hypoxia as well as prolonged renal hypoperfusion may be responsible for his kidney injury.

Adenosine A2A receptors and ATP-activated K+ (KATP) channels contribute to part of the cerebral vasodilatory response to systemic hypoxia, but other mediators are likely involved. Epoxyeicosatrienoic acids (EETs) are cerebral vasodilators and are released from astrocytes exposed to hypoxia. Moreover, stimulation of metabotropic glutamate receptors (mGluR) produces vasodilation by an EET-dependent mechanism. Here, we tested the hypothesis that EET signaling and mGluR activation contribute to hypoxic vasodilation. Laser-Doppler flow was measured over cerebral cortex of anesthetized rats subjected to stepwise reductions in arterial oxygen saturation to 50-70%. Hypoxic reactivity was calculated as the slope of the change in laser-Doppler flow vs. the reciprocal of arterial oxygen content. Hypoxic reactivity significantly decreased from 9.2 ± 1.9 (±95% confidence interval) in controls with vehicle treatment to 2.6 ± 1.4 with the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid, to 3.0 ± 1.5 with the EET synthesis inhibitor MS-PPOH, to 1.9 ± 2.3 with the combined mGluR subtype 1 and 5 antagonists 2-methyl-6-(phenylethynyl)pyridine and LY367385 , to 5.6 ± 1.2 with the KATP channel inhibitor glibenclamide, and to 5.8 ± 2.3 with the A2A receptor antagonist SCH58261. However, reactivity was not significantly altered by the A2B receptor antagonist MRS1754 (6.7 ± 1.8; P = 0.28 Dunnett's test) or by the 20-hydroxyeicosatetraenoic acid synthesis inhibitor HET0016 (7.5 ± 2.3; P = 0.6). These data indicate that, in addition to the known contributions of A2A receptors and KATP channels to the increase in cerebral blood flow during hypoxia, EETs and mGluRs make a major contribution, possibly by mGluR stimulation and hypoxia-induced release of EETs. In contrast, A2B receptors do not make a major contribution, and 20-hydroxyeicosatetraenoic acid does not significantly limit hypoxic vasodilation.

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O2 in 88% N2 as well as breathing 15% O2 in 85% N2. Oxygen saturation in a retinal artery (SO2art) and an adjacent retinal vein (SO2vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% ( P < 0.001) and 30.0 ± 20.9% ( P < 0.001) during 12% and 15% O2 breathing, respectively. SO2art as well as SO2vein decreased during both 12% O2 breathing (SO2art: −11.2 ± 4.3%, P < 0.001; SO2vein: −3.9 ± 8.5%, P = 0.012) and 15% O2 breathing (SO2art: −7.9 ± 3.6%, P < 0.001; SO2vein: −4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: −28.9 ± 18.7%; 15% O2: −19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O2: −2.8 ± 18.9%, P = 0.65; 15% O2: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.