Search Results (31)

Reduced oxygen availability, or hypoxia, is an environmental stress factor that modulates cellular and systemic functions. It plays a significant role in both physiological and pathological conditions, including tissue regeneration, where it influences angiogenesis, metabolic adaptation, inflammation, and stem cell activity. Hypoxia-inducible factors (HIFs) orchestrate these responses by activating genes that promote survival and repair, although HIF-independent mechanisms, particularly those related to mitochondrial function, are also involved. Depending on its duration and severity, hypoxia may exert either beneficial or harmful effects, ranging from enhanced regeneration to fibrosis or maladaptive remodeling. This review explores the systemic and cellular effects of acute, chronic, intermittent, and preconditioning hypoxia in the context of tissue regeneration. Hypoxia-driven responses are examined across tissues, organs, and complex structures, including the heart, muscle, bone, vascular structures, nervous tissue, and appendages such as tails. We analyze findings from animal models and in vitro studies, followed by biomedical and pharmacological strategies designed to modulate hypoxia and their initial exploration in clinical settings. These strategies involve regulatory molecules, signaling pathways, and microRNA activity, which are investigated across species with diverse regenerative capacities to identify mechanisms that may be conserved or divergent among taxa. Lastly, we emphasize the need to standardize hypoxic conditions to improve reproducibility and highlight their therapeutic potential when precisely controlled. Full article

Microcirculatory oscillations known as flowmotion are a recognized feature of blood flow that reflect the functional state of the vascular system. Many diseases are associated with impaired flowmotion, especially diseases that are accompanied by hypoxia. Low-frequency myogenic oscillations (0.052–0.15 Hz) are an important regulator of microvascular adaptation to hypoxia. Here, we study the myogenic component of flowmotion using the FMSF–PORH (Flow Mediated Skin Fluorescence–Post Occlusive Reactive Hyperemia) technique. Myogenic oscillations were strongly activated under hypoxic conditions caused by occlusion of the brachial artery or intermittent hypoxic treatment. A strong correlation was noted between the hypoxia sensitivity parameter HS (the intensity of myogenic oscillations activated by hypoxia) and the normoxic myogenic flowmotion parameter VM (the intensity of myogenic oscillations under normoxic conditions). If HS is considered as a direct measure of the microcirculation response to hypoxia, then VM can be considered a measure of the microcirculation’s readiness to provide this response. The predictive value of the VM parameter is presented. The assessment of myogenic activity under normoxia conditions could thus provide a simple and rapid diagnostic tool for health care practitioners. Full article

Background/Objectives: Post-COVID-19 condition (PCC), also known as long COVID, has emerged as a recognized syndrome affecting millions of people worldwide, significantly impairing their quality of life. Currently, no effective therapeutic options are available to manage this condition. The objective of the present study was to evaluate the long-term effects of personalized, algorithm-based intermittent hypoxia–hyperoxia conditioning (IHHC) on quality of life and pain in patients with PCC. Methods: This open-label cohort study included 199 PCC patients, aged 11–87 years (female-to-male ratio: 67:33) and experiencing moderate-to-severe fatigue, between 1 January 2020 and 31 December 2023. Each patient received an algorithm-based treatment plan tailored to their demographics, symptom duration, and baseline pain (NRS) and quality of life (SF-36) scores. Patients received an average of six treatment sessions (range: 2–21), each consisting of intermittent hypoxic–hyperoxic cycles, with hypoxia (9–13% O₂) lasting 3–8 min and hyperoxia (34–36% O₂) lasting 1–3 min. The primary outcomes were changes in the NRS and SF-36 scores at the 6-week and 6-month follow-ups. Results: At the 6-week follow-up after treatment initiation, the SF-36 scores increased by 102 points (p < 0.001, 95% CI: 78.4–127), and this improvement persisted at the 6-month follow-up (Δ106, p < 0.001, 95% CI: 57.0–154). Pain was reduced by 28–32% at both follow-up time points, exceeding the clinically relevant threshold. Health transition scores indicated a patient-perceived improvement in health status. Conclusions: In this study, a personalized, algorithm-based IHHC alleviated pain and improved quality of life in patients suffering from persistent long-term sequelae after COVID-19 infection. The effects were sustained for up to six months. Further research is warranted to elucidate the mechanisms underlying IHHC’s therapeutic effects in this patient population. Full article

Comprehending the immune defense mechanisms of new aquaculture species, such as the Chilean meagre (Cilus gilberti), is essential for sustaining large-scale production. Two bioassays were conducted to assess the impact of acute and intermittent hypoxia on the antibacterial activity of juvenile Chilean meagre epidermal mucus against the potential pathogens Vibrio anguillarum and Vibrio ordalii. Lysozyme and peroxidase activities were also measured. In general, fish exposed to hypoxia showed a 9–30% reduction in mucus antibacterial activity at the end of hypoxic periods and after stimulation with lipopolysaccharide. However, following water reoxygenation, the activity of non-stimulated fish was comparable to that of fish in normoxic conditions, inhibiting bacterial growth by 35–52%. In the case of fish exposed to chronic hypoxia, the response against V. anguillarum increased by an additional 19.8% after 6 days of control inoculation. Lysozyme exhibited a similar pattern, while no modulation of peroxidase activity was detected post-hypoxia. These results highlight the resilience of C. gilberti to dissolved oxygen fluctuations and contribute to understanding the potential of mucus in maintaining the health of cultured fish and the development of future control strategies. Full article

This study explores the effects of normobaric hypoxia and intermittent hypoxic training (IHT) on the physiological condition of the cardiac muscle in swimmers. Hypoxia has been reported to elicit both beneficial and adverse changes in the cardiovascular system, but its impact on the myocardium during acute exercise and altitude/hypoxic training remains less understood. We aimed to determine how a single bout of intense interval exercise and a four-week period of high-intensity endurance training under normobaric hypoxia affect cardiac marker activity in swimmers. Sixteen young male swimmers were divided into two groups: one undergoing training in hypoxia and the other in normoxia. Cardiac markers, including troponin I and T (cTnI and cTnT), heart-type fatty acid-binding protein (H-FABP), creatine kinase-MB isoenzyme (CK-MB), and myoglobin (Mb), were analyzed to assess the myocardium’s response. We found no significant differences in the physiological response of the cardiac muscle to intense physical exertion between hypoxia and normoxia. Four weeks of IHT did not alter the resting levels of cTnT, cTnI, and H-FABP, but it resulted in a noteworthy decrease in the resting concentration of CK-MB, suggesting enhanced cardiac muscle adaptation to exercise. In contrast, a reduction in resting Mb levels was observed in the control group training in normoxia. These findings suggest that IHT at moderate altitudes does not adversely affect cardiac muscle condition and may support cardiac muscle adaptation, affirming the safety and efficacy of IHT as a training method for athletes. Full article

The aim of this study was to investigate the effects of different protocols of moderate-intensity intermittent hypoxic training in patients who had recovered from COVID-19 on quality of life (QoL) and mental health. The sample of this clinical trial-controlled double-blind study consisted of 67 participants aged 30–69 years, who were organized randomly according to Normoxia, Hypoxia, Hypoxia Recovery or Control Group. Eight weeks of cycle ergometer training were performed with a frequency of three training sessions per week in normoxic or hypoxic conditions (with or without hypoxic recovery). Health-related QoL and Mental Health Status were evaluated by 12-Item Short Form Survey and Depression Anxiety and Stress Scale instruments, respectively. All training groups improved the QoL’s physical dimensions (Baseline–Post: Normoxia Group 42.1 (11.0)–48.7 (7.0), Hypoxia Group 46.9 (11.8)–53.5 (6.6) and Hypoxia Recovery Group 45.8 (9.2)–51.1 (5.3)) and mental dimensions (Baseline–Post: Normoxia Group 48.8 (7.9)–54.6 (4.6), Hypoxia Group 45.2 (7.7)–53.2 (3.8) and Hypoxia Recovery Group 46.5 (9.7)–52.0 (9.9)). Regarding mental health outcomes, all training groups decreased depressive symptoms (66.7% Normoxia, 31.2% Hypoxia Recovery and 31% Hypoxia groups), anxiety symptoms (46.5% Normoxia, 45.9% Hypoxia Recovery and 39.5% in the Hypoxia groups) and stress symptoms (40.6% Normoxia, 36.3% Hypoxia Recovery and 22.1% Hypoxia groups). Significant statistical difference was not found between groups. Normoxic and hypoxic training showed a similar effect on QoL and the mental health of Brazilian adults who had recovered from COVID-19. Full article

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may increase the risk of cancer development and a poor cancer prognosis. TAMs of the M2 phenotype, together with the intermittent hypoxic environment within the tumor, drive tumor aggressiveness. However, the mechanism of TAMs in IH remains unclear. In our study, IH induced the recruitment of macrophages, and IH-induced M2-like TAMs promoted glycolysis in laryngeal cancer cells through hexokinase 1. The hexokinase inhibitor 2-deoxy-D-glucose and HK1 shRNA were applied to verify this finding, confirming that M2-like TAMs enhanced glycolysis in laryngeal cancer cells through HK1 under intermittent hypoxic conditions. Comprehensive RNA-seq analysis disclosed a marked elevation in the expression levels of the transcription factor ZBTB10, while evaluation of a laryngeal cancer patient tissue microarray demonstrated a positive correlation between ZBTB10 and HK1 expression in laryngeal carcinoma. Knockdown of ZBTB10 decreased HK1 expression, and overexpression of ZBTB10 increased HK1 expression in both laryngeal cancer cells and 293T cells. The luciferase reporter assay and Chromatin immunoprecipitation assay confirmed that ZBTB10 directly bound to the promoter region of HK1 and regulated the transcriptional activity of HK1. Finally, the CLEC3B level of the M2 supernatant is significantly higher in the IH group and showed a protumor effect on Hep2 cells. As ZBTB10-mediated regulation of HK1 affects glycolysis in laryngeal cancer, our findings may provide new potential therapeutic targets for laryngeal cancer. Full article

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic–hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 μmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques. Full article

Hypobaric hypoxia under chromic conditions triggers hypoxic pulmonary vasoconstriction (HPV) and right ventricular hypertrophy (RVH). The role of zinc (Zn) under hypoxia is controversial and remains unclear. We evaluated the effect of Zn supplementation in prolonged hypobaric hypoxia on HIF2α/MTF-1/MT/ZIP12/PKCε pathway in the lung and RVH. Wistar rats were exposed to hypobaric hypoxia for 30 days and randomly allocated into three groups: chronic hypoxia (CH); intermittent hypoxia (2 days hypoxia/2 days normoxia; CIH); and normoxia (sea level control; NX). Each group was subdivided (n = 8) to receive either 1% Zn sulfate solution (z) or saline (s) intraperitoneally. Body weight, hemoglobin, and RVH were measured. Zn levels were evaluated in plasma and lung tissue. Additionally, the lipid peroxidation levels, HIF2α/MTF-1/MT/ZIP12/PKCε protein expression and pulmonary artery remodeling were measured in the lung. The CIH and CH groups showed decreased plasma Zn and body weight and increased hemoglobin, RVH, and vascular remodeling; the CH group also showed increased lipid peroxidation. Zn administration under hypobaric hypoxia upregulated the HIF2α/MTF-1/MT/ZIP12/PKCε pathway and increased RVH in the intermittent zinc group. Under intermittent hypobaric hypoxia, Zn dysregulation could participate in RVH development through alterations in the pulmonary HIF2α/MTF1/MT/ZIP12/PKCε pathway. Full article

Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in tumor biochemistry, we investigated the expression dynamics of CA IX in normoxia, hypoxia and intermittent hypoxia, which are typical conditions experienced by tumor cells in aggressive carcinomas. We correlated the CA IX epitope expression dynamics with extracellular pH acidification and with viability of CA IX-expressing cancer cells upon treatment with CA IX inhibitors (CAIs) in colon HT-29, breast MDA-MB-231 and ovarian SKOV-3 tumor cell models. We observed that the CA IX epitope expressed under hypoxia by these cancer cells is retained in a significant amount upon reoxygenation, probably to preserve their proliferation ability. The extracellular pH drop correlated well with the level of CA IX expression, with the intermittent hypoxic cells showing a similar pH drop to fully hypoxic ones. All cancer cells showed higher sensitivity to CA IX inhibitors (CAIs) under hypoxia as compared to normoxia. The tumor cell sensitivity to CAIs under hypoxia and intermittent hypoxia were similar and higher than in normoxia and appeared to be correlated with the lipophilicity of the CAI. Full article

Cyclooxygenase 2 (COX2) inhibitors have been demonstrated to protect against hypoxia pathogenesis in several investigations. It has also been utilized as an adjuvant therapy in the treatment of COVID-19. COX inhibitors, which have previously been shown to be effective in treating previous viral and malarial infections are strong candidates for improving the COVID-19 therapeutic doctrine. However, another COX inhibitor, ibuprofen, is linked to an increase in the angiotensin-converting enzyme 2 (ACE2), which could increase virus susceptibility. Hence, inhibiting COX2 via therapeutics might not always be protective and we need to investigate the downstream molecules that may be involved in hypoxia environment adaptation. Research has discovered that people who are accustomed to reduced oxygen levels at altitude may be protected against the harmful effects of COVID-19. It is important to highlight that the study’s conclusions only applied to those who regularly lived at high altitudes; they did not apply to those who occasionally moved to higher altitudes but still lived at lower altitudes. COVID-19 appears to be more dangerous to individuals residing at lower altitudes. The downstream molecules in the (COX2) pathway have been shown to adapt in high-altitude dwellers, which may partially explain why these individuals have a lower prevalence of COVID-19 infection. More research is needed, however, to directly address COX2 expression in people living at higher altitudes. It is possible to mimic the gene–environment interaction of higher altitude people by intermittent hypoxia training. COX-2 adaptation resulting from hypoxic exposure at altitude or intermittent hypoxia exercise training (IHT) seems to have an important therapeutic function. Swimming, a type of IHT, was found to lower COX-2 protein production, a pro-inflammatory milieu transcription factor, while increasing the anti-inflammatory microenvironment. Furthermore, Intermittent Hypoxia Preconditioning (IHP) has been demonstrated in numerous clinical investigations to enhance patients’ cardiopulmonary function, raise cardiorespiratory fitness, and increase tissues’ and organs’ tolerance to ischemia. Biochemical activities of IHP have also been reported as a feasible application strategy for IHP for the rehabilitation of COVID-19 patients. In this paper, we aim to highlight some of the most relevant shared genes implicated with COVID-19 pathogenesis and hypoxia. We hypothesize that COVID-19 pathogenesis and hypoxia share a similar mechanism that affects apoptosis, proliferation, the immune system, and metabolism. We also highlight the necessity of studying individuals who live at higher altitudes to emulate their gene–environment interactions and compare the findings with IHT. Finally, we propose COX2 as an upstream target for testing the effectiveness of IHT in preventing or minimizing the effects of COVID-19 and other oxygen-related pathological conditions in the future. Full article

Hypoxia may be associated with alterations in bone remodeling, but the published results are contradictory. The aim of this study was to characterize the bone morphometry changes subject to hypoxia for a better understanding of the bone response to hypoxia and its possible clinical consequences on the bone metabolism. This study analyzed the bone morphometry parameters by micro-computed tomography (μCT) in rat and guinea pig normobaric hypoxia models. Adult male and female Wistar rats were exposed to chronic hypoxia for 7 and 15 days. Additionally, adult male guinea pigs were exposed to chronic hypoxia for 15 days. The results showed that rats exposed to chronic constant and intermittent hypoxic conditions had a worse trabecular and cortical bone health than control rats (under a normoxic condition). Rats under chronic constant hypoxia were associated with a more deteriorated cortical tibia thickness, trabecular femur and tibia bone volume over the total volume (BV/TV), tibia trabecular number (Tb.N), and trabecular femur and tibia bone mineral density (BMD). In the case of chronic intermittent hypoxia, rats subjected to intermittent hypoxia had a lower cortical femur tissue mineral density (TMD), lower trabecular tibia BV/TV, and lower trabecular thickness (Tb.Th) of the tibia and lower tibia Tb.N. The results also showed that obese rats under a hypoxic condition had worse values for the femur and tibia BV/TV, tibia trabecular separation (Tb.Sp), femur and tibia Tb.N, and BMD for the femur and tibia than normoweight rats under a hypoxic condition. In conclusion, hypoxia and obesity may modify bone remodeling, and thus bone microarchitecture, and they might lead to reductions in the bone strength and therefore increase the risk of fragility fracture. Full article

Background: Hypoxic brain injury is a condition caused by restricted oxygen supply to the brain. Several studies have reported cognitive decline, particularly in spatial memory, after exposure to intermittent hypoxia (IH). However, the effect and mechanism of action of IH exposure on cognition have not been evaluated by analyzing gene expression after transcranial direct current stimulation (tDCS). Hence, the purpose of this study was to investigate the effects of tDCS on gene regulation and cognition in a rat model of IH-induced brain injury. Methods: Twenty-four 10-week-old male Sprague–Dawley rats were divided into two groups: IH exposed rats with no stimulation and IH-exposed rats that received tDCS. All rats were exposed to a hypoxic chamber containing 10% oxygen for twelve hours a day for five days. The stimulation group received tDCS at an intensity of 200 µA over the frontal bregma areas for 30 min each day for a week. As a behavior test, the escape latency on the Morris water maze (MWM) test was measured to assess spatial memory before and after stimulation. After seven days of stimulation, gene microarray analysis was conducted with a KEGG mapper tool. Results: Although there were no significant differences between the groups before and after stimulation, there was a significant effect of time and a significant time × group interaction on escape latency. In the microarray analysis, significant fold changes in 12 genes related to neurogenesis were found in the stimulation group after tDCS (p < 0.05, fold change > 2 times, the average of the normalized read count (RC) > 6 times). The highly upregulated genes in the stimulation group after tDCS were SOS, Raf, PI3K, Rac1, IRAK, and Bax. The highly downregulated genes in the stimulation group after tDCS were CHK, Crk, Rap1, p38, Ras, and NF-kB. Conclusion: In this study, we confirmed that SOS, Raf, PI3K, Rac1, IRAK, and Bax were upregulated and that CHK, Crk, Rap1, p38, Ras, and NF-kB were downregulated in a rat model of IH-induced brain injury after application of tDCS. Full article

The Lusitanian toadfish, Halobatrachus didactylus is a marine teleost found in coastal lagoons and river estuaries, often exposed to important changes in salinity, temperature and reduced oxygen. Sedentary species, with strong site fidelity and low migratory ability along the temperature gradient such as this may be especially impacted by climate change. We aimed at establishing the tolerance limits to acute temperature and oxygen changes, and evaluate respiratory and metabolic responses in chronic control, warm and hypoxic (35% O₂) conditions. Critical temperature maximum (CTmax) was determined in 12 individuals exposed to a temperature ramp of 3 °C per hour starting at 18 °C, and was found to be 34.8 ± 0.66 °C. Critical oxygen level (PO₂crit) was determined in 8 fish at 18 °C while performing intermittent respirometry and oxygen depletion was created by nitrogen injection in the tank. PO₂crit was calculated as the inflexion point between oxyregulation and oxyconformation, which was found to be around 1.2 mgO₂/L, but fish survived down to 3% O₂, recovering from 0.2 mgO₂/L but showing increased hematocrit (Hct), red blood cell (RBC) counts and blood pH. We also quantified routine aerobic scope and daily activity patterns, finding this fish to be extremely sedentary. H. didactylus showed one of the lowest daytime basal metabolic rates (MR) found in the literature but activity increased significantly at night (over two-fold when closed inside the metabolic chambers). The effect of temperature on metabolic rate (MR) was evaluated using a temperature ramp ranging from 8 to 32 °C (1 °C/h). Acute temperature changes resulted in a steady increase in MR up to circa 29 °C, beyond which MR become increasingly variable, especially among smaller individuals. Indeed, small fish appear to show high- and low-MR groups, and were more susceptible to heat and hypoxia than larger individuals. In chronic acclimation, the MR was increased by 3- and 4-fold (hypoxia vs. normoxia) in fish at 28 °C in relation to those at 12 °C. Standard MR were not statistically different between normoxia and hypoxia at 12 °C, but maximum MR in hypoxia was only about 2/3 of that in normoxia. Fish in high temperature lost weight (mean −3.1%) and had higher metabolism, while in low temperature, weight increased (mean +9.3%) and metabolism was low, and HIS was significantly lower in high temperature groups. Fish in hypoxic conditions showed consistently high Hct but not RBC or hemoglobin (Hb). Overall this study indicates that H. didactylus is highly tolerant to hypoxia and temperature variations. It remains to be seen if other populations along the Atlantic coast show similar metrics. The measured CTmax is close to the actual maximum temperature possible to experience in Ria Formosa ponds during summer, and it would not be unexpected to find this species establishing stable populations in other regions if climate change forces it out of its actual distribution. Full article

Cells respond to reduced oxygen availability predominately by activation of the hypoxia-inducible factor (HIF) pathway. HIF activation upregulates hundreds of genes that help cells survive in the reduced oxygen environment. The aim of this study is to determine whether chemical-induced HIF accumulation mimics all aspects of the hypoxic response of cells. We compared the effects of dimethyloxalylglycine (DMOG) (a HIF stabiliser) on PC12 cells cultured in air oxygen (20.9% O_2, AO) with those cultured in either intermittent 20.9% O₂ to 2% O₂ (IH) or constant 2% O₂ (CN). Cell viability, cell cycle, HIF accumulation, reactive oxygen species (ROS) formation, mitochondrial function and differentiation were used to characterise the PC12 cells and evaluate the impact of DMOG. IH and CN culture reduced the increase in cell numbers after 72 and 96 h and MTT activity after 48 h compared to AO culture. Further, DMOG supplementation in AO induced a dose-dependent reduction in the increase in PC12 cell numbers and MTT activity. IH-cultured PC12 cells displayed increased and sustained HIF-1 expression over 96 h. This was accompanied by increased ROS and mitochondrial burden. PC12 cells in CN displayed little changes in HIF-1 expression or ROS levels. DMOG (0.1 mM) supplementation resulted in an IH-like HIF-1 profile. The mitochondrial burden and action potential of DMOG-supplemented PC12 cells did not mirror those seen in other conditions. DMOG significantly increased S phase cell populations after 72 and 96 h. No significant effect on PC12 cell differentiation was noted with IH and CN culture without induction by nerve growth factor (NGF), while DMOG significantly increased PC12 cell differentiation with and without NGF. In conclusion, DMOG and reduced oxygen levels stabilise HIF and affect mitochondrial activity and cell behaviour. However, DMOG does not provide an accurate replication of the reduced oxygen environments. Full article