The term “normobaric oxygen paradox” (NOP), describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as oxygen shortage, and resulting in up-regulation of the Hypoxia-inducible factor 1α (HIF-1α) transcription factor activity. The molecular characteristics of this response have not been yet fully characterized. Herein, we report the activation time trend of oxygen-sensitive transcription factors in human peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects after one hour of exposure to mild (MH), high (HH) and very high (VHH) hyperoxia, corresponding to 30%, 100%, 140% O₂, respectively. Our observations confirm that MH is perceived as a hypoxic stress, characterized by the activation of HIF-1α and Nuclear factor (erythroid-derived 2)-like 2 (NRF2), but not Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Conversely, HH is associated to a progressive loss of NOP response and to an increase in oxidative stress leading to NRF2 and NF-kB activation, accompanied by the synthesis of glutathione (GSH). After VHH, HIF-1α activation is totally absent and oxidative stress response, accompanied by NF-κB activation, is prevalent. Intracellular GSH and Matrix metallopeptidase 9 (MMP-9) plasma levels parallel the transcription factors activation pattern and remain elevated throughout the observation time. In conclusion, our study confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-κB activation in the first 24 h post exposure.

Hyperbaric oxygen therapy (HBOT) is a therapeutical approach based on exposure to pure oxygen in an augmented atmospheric pressure. Although it has been used for years, the exact kinetics of the reactive oxygen species (ROS) between different pressures of hyperbaric oxygen exposure are still not clearly evidenced. In this study, the metabolic responses of hyperbaric hyperoxia exposures for 1 h at 1.4 and 2.5 ATA were investigated. Fourteen healthy non-smoking subjects (2 females and 12 males, age: 37.3 ± 12.7 years old (mean ± SD), height: 176.3 ± 9.9 cm, and weight: 75.8 ± 17.7 kg) volunteered for this study. Blood samples were taken before and at 30 min, 2 h, 24 h, and 48 h after a 1 h hyperbaric hyperoxic exposure. The level of oxidation was evaluated by the rate of ROS production, nitric oxide metabolites (NOx), and the levels of isoprostane. Antioxidant reactions were assessed through measuring superoxide dismutase (SOD), catalase (CAT), cysteinylglycine, and glutathione (GSH). The inflammatory response was measured using interleukine-6, neopterin, and creatinine. A short (60 min) period of mild (1.4 ATA) and high (2.5 ATA) hyperbaric hyperoxia leads to a similar significant increase in the production of ROS and antioxidant reactions. Immunomodulation and inflammatory responses, on the contrary, respond proportionally to the hyperbaric oxygen dose. Further research is warranted on the dose and the inter-dose recovery time to optimize the potential therapeutic benefits of this promising intervention.

Inflammation is an adaptive response to both external and internal stimuli including infection, trauma, surgery, ischemia-reperfusion, or malignancy. A number of studies indicate that physical activity is an effective means of reducing acute systemic and low-level inflammation occurring in different pathological conditions and in the recovery phase after disease. As a proof-of-principle, we hypothesized that low-intensity workout performed under modified oxygen supply would elicit a “metabolic exercise” inducing a hormetic response, increasing the metabolic load and oxidative stress with the same overall effect expected after a higher intensity or charge exercise. Herein, we report the effect of a 5-week low-intensity, non-training, exercise program in a group of young healthy subjects in combination with the exposure to hyperoxia (30% and 100% pO₂, respectively) or light hypoxia (15% pO₂) during workout sessions on several inflammation and oxidative stress parameters, namely hemoglobin (Hb), redox state, nitric oxide metabolite (NOx), inducible nitric oxide synthase (iNOS), inflammatory cytokine expression (TNF-α, interleukin (IL)-6, IL-10), and renal functional biomarkers (creatinine, neopterin, and urates). We confirmed our previous reports demonstrating that intermittent hyperoxia induces the normobaric oxygen paradox (NOP), a response overlapping the exposure to hypoxia. Our data also suggest that the administration of modified air composition is an expedient complement to a light physical exercise program to achieve a significant modulation of inflammatory and immune parameters, including cytokines expression, iNOS activity, and oxidative stress parameters. This strategy can be of pivotal interest in all those conditions characterized by the inability to achieve a sufficient workload intensity, such as severe cardiovascular alterations and articular injuries failing to effectively gain a significant improvement of physical capacity.

Objective: We aimed to evaluate the feasibility of an online High-Intensity Interval Training (HIIT) program on clinical psychological symptoms in higher education students in the context of the COVID-19 pandemic lockdown.Materials and Methods: During the lockdown, 30 students aged 18–25 years, who had been screened previously with a cut-off score ≥5 in the Generalized Anxiety Disorder-7 (GAD-7) questionnaire, were randomly assigned to either the 4-week HIIT program with three sessions per week conducted through online videos, or a no-intervention control group. The primary outcome was the feasibility assessment. The secondary outcome was a psychological self-report with the 21-items Depression, Anxiety, and Stress Scale (DASS-21). Assessment and intervention were performed in compliance with social distancing rules.Results: Two participants in the HIIT were lost to follow-up, leaving 13 participants vs. 15 in the control group. We observed high adherence (87%) and complete safety for mental and physical status with the HIIT intervention delivered by online videos. The Mann-Whitney test demonstrated a significant (group × time, P-Value = 0.046) reduction of clinical stress symptoms and a trend (group × time, P-Value = 0.08) toward reduction of clinical depression symptoms, both favoring the HIIT group. No significant (group × time, P-Value = 0.118) interaction was found for anxiety symptoms.Conclusion: The online HIIT program was found to be feasible and safe in a clinical sample of young adults, who were experiencing social and physical restrictions due to COVID-19. HIIT reduced stress and depressive symptoms and thus these preliminary results show promise for broader application among higher education students during the present lockdown necessitated by the global COVID-19 health crisis.

Oxygen is a powerful trigger for cellular reactions, but there are few comparative investigations assessing the effects over a large range of partial pressures. We investigated a metabolic response to single exposures to either normobaric (10%, 15%, 30%, 100%) or hyperbaric (1.4 ATA, 2.5 ATA) oxygen. Forty-eight healthy subjects (32 males/16 females; age: 43.7 ± 13.4 years, height: 172.7 ± 10.07 cm; weight 68.4 ± 15.7 kg) were randomly assigned, and blood samples were taken before and 2 h after each exposure. Microparticles (MPs) expressing proteins specific to different cells were analyzed, including platelets (CD41), neutrophils (CD66b), endothelial cells (CD146), and microglia (TMEM). Phalloidin binding and thrombospondin-1 (TSP), which are related to neutrophil and platelet activation, respectively, were also analyzed. The responses were found to be different and sometimes opposite. Significant elevations were identified for MPs expressing CD41, CD66b, TMEM, and phalloidin binding in all conditions but for 1.4 ATA, which elicited significant decreases. Few changes were found for CD146 and TSP. Regarding OPB, further investigation is needed to fully understand the future applications of such findings.

Oxygen is a powerful trigger for cellular reactions and is used in many pathologies, including oxidative stress. However, the effects of oxygen over time and at different partial pressures remain poorly understood. In this study, the metabolic responses of normobaric oxygen intake for 1 h to mild (30%) and high (100%) inspired fractions were investigated. Fourteen healthy non-smoking subjects (7 males and 7 females; age: 29.9 ± 11.1 years, height: 168.2 ± 9.37 cm; weight: 64.4 ± 12.3 kg; BMI: 22.7 ± 4.1) were randomly assigned in the two groups. Blood samples were taken before the intake at 30 min, 2 h, 8 h, 24 h, and 48 h after the single oxygen exposure. The level of oxidation was evaluated by the rate of reactive oxygen species (ROS) and the levels of isoprostane. Antioxidant reactions were observed by total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT). The inflammatory response was measured using interleukin-6 (IL-6), neopterin, creatinine, and urates. Oxidation markers increased from 30 min on to reach a peak at 8 h. From 8 h post intake, the markers of inflammation took over, and more significantly with 100% than with 30%. This study suggests a biphasic response over time characterized by an initial “permissive oxidation” followed by increased inflammation. The antioxidant protection system seems not to be the leading actor in the first place. The kinetics of enzymatic reactions need to be better studied to establish therapeutic, training, or rehabilitation protocols aiming at a more targeted use of oxygen.