BACKGROUND: Parkinson\'s disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD.
METHODS: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson\'s Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction.
CONCLUSIONS: This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD.
BACKGROUND: ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023).

Guo, Hai, Linjie Cheng, Dilihumaier Duolikun, and Qiaoling Yao. Aerobic exercise training under normobaric hypoxic conditions to improve glucose and lipid metabolism in overweight and obese individuals: a systematic review and meta-analysis. High Alt Med Biol. 24:312-320, 2023. Background: Obesity is a critical public health issue around the world, reaching epidemic proportions in some countries. However, only a few studies have examined the effects of hypoxic training on metabolic parameters in an obese population. This systematic review and meta-analysis aimed to determine the effects of aerobic exercise training under normobaric hypoxic conditions versus normoxic training in improving glucose and lipid metabolism in obese individuals. Methods: A systematic search of PubMed, EMBASE, Web of Science, and Wan Fang databases (up to August 2021) was performed to identify randomized controlled trials (RCTs) of overweight or obese human subjects eligible for inclusion. Main study endpoints were changes in body mass index (BMI), waist/hip (W/H) ratio, leptin, blood glucose and insulin levels, as well as blood lipids between hypoxic and normoxic conditioning. Results: Fourteen RCTs with a total of 413 subjects qualified for inclusion. Pooled analyses revealed that BMI (d = 0.38), W/H ratio (d = 0), blood glucose (d = 0.01), and triglyceride (d = -2.27) were not significantly different between aerobic exercise training under hypoxic and normoxic conditions. However, significant differences were found in heart rate at rest (d = -4.50) between aerobic exercise training under hypoxic versus normoxic conditions. Conclusions: In conclusion, no significant benefits were noted in aerobic exercise training under hypoxic conditions over normoxic conditions in overweight or obese individuals. However, the maximum training heart rate mm was significantly higher under hypoxic conditions than under normoxic conditions. Future studies with larger samples controlling for exercise-related parameters, and addressing the potential modifying effects of level of hypoxia, sex, or age on the role of hypoxic exercise training are warranted. PROSPERO registration number: CRD42020221680.

The current pandemic of surgical complications necessitates urgent and pragmatic innovation to reduce postoperative morbidity and mortality, which are associated with poor pre-operative fitness and anaemia. Exercise prehabilitation is a compelling strategy, but it has proven difficult to establish that it improves outcomes either in isolation or as part of a multimodal approach. Simulated altitude exposure improves performance in athletes and offers a novel potential means of improving cardiorespiratory and metabolic fitness and alleviating anaemia within the prehabilitation window. We aimed to provide an initial physiological foundation for \'altitude prehabilitation\' by determining the physiological effects of one week of simulated altitude (FI O2 15%, equivalent to approximately 2438 m (8000 ft)) in older sedentary volunteers. The study used a randomised, double-blind, sham-controlled crossover design. Eight participants spent counterbalanced normoxic and hypoxic weeks in a residential hypoxia facility and underwent repeated cardiopulmonary exercise tests. Mean (SD) age of participants was 64 (7) y and they were unfit, with mean (SD) baseline anaerobic threshold 12 (2) ml.kg-1 .min-1 and mean (SD) peak V̇O2 15 (3) ml.kg-1 .min-1 . Hypoxia was mild (mean (SD) Sp O2 93 (2) %, p < 0.001) and well-tolerated. Despite some indication of greater peak exercise capacity following hypoxia, overall there was no effect of simulated altitude on anaerobic threshold or peak V̇O2 . However, hypoxia induced a substantial increase in mean (SD) haemoglobin of 1.5 (2.7) g.dl-1 (13% increase, p = 0.028). This study has established the concept and feasibility of \'altitude prehabilitation\' and demonstrated specific potential for improving haematological fitness. Physiologically, there is value in exploring a possible role for simulated altitude in pre-operative optimisation.

Adipose-derived mesenchymal stromal cells (MSC(AT)) display immunomodulatory and angiogenic properties, but an improved understanding of quantitative critical quality attributes (CQAs) that inform basal MSC(AT) fitness ranges for immunomodulatory and/or angiogenic applications is urgently needed for effective clinical translation. We constructed an in vitro matrix of multivariate readouts to identify putative CQAs that were sensitive enough to discriminate between specific critical processing parameters (CPPs) chosen for their ability to enhance MSC immunomodulatory and angiogenic potencies, with consideration for donor heterogeneity. We compared 3D aggregate culture conditions (3D normoxic, 3D-N) and 2D hypoxic (2D-H) culture as non-genetic CPP conditions that augment immunomodulatory and angiogenic fitness of MSC(AT). We measured multivariate panels of curated genes, soluble factors, and morphometric features for MSC(AT) cultured under varying CPP and licensing conditions, and we benchmarked these against two functional and therapeutically relevant anchor assays - in vitro monocyte/macrophage (MΦ) polarization and in vitro angiogenesis. Our results showed that varying CPP conditions was the primary driver of MSC(AT) immunomodulatory fitness; 3D-N conditions induced greater MSC(AT)-mediated MΦ polarization toward inflammation-resolving subtypes. In contrast, donor heterogeneity was the primary driver of MSC(AT) angiogenic fitness. Our analysis further revealed panels of putative CQAs with minimum and maximum values that consisted of twenty MSC(AT) characteristics that informed immunomodulatory fitness ranges, and ten MSC(AT) characteristics that informed angiogenic fitness ranges. Interestingly, many of the putative CQAs consisted of angiogenic genes or soluble factors that were inversely correlated with immunomodulatory functions (THBS1, CCN2, EDN1, PDGFA, VEGFA, EDIL3, ANGPT1, and ANG genes), and positively correlated to angiogenic functions (VEGF protein), respectively. We applied desirability analysis to empirically rank the putative CQAs for MSC(AT) under varying CPP conditions and donors to numerically identify the desirable CPP conditions or donors with maximal MSC(AT) immunomodulatory and/or angiogenic fitness. Taken together, our approach enabled combinatorial analysis of the matrix of multivariate readouts to provide putative quantitative CQAs that were sensitive to variations in select CPPs that enhance MSC immunomodulatory/angiogenic potency, and donor heterogeneity. These putative CQAs may be used to prospectively screen potent MSC(AT) donors or cell culture conditions to optimize for desired basal MSC(AT) immunomodulatory or angiogenic fitness.

Background: It was recently shown that intermittent hypoxic-hyperoxic exposure (IHHE) applied prior to a multimodal training program promoted additional improvements in cognitive and physical performance in geriatric patients compared to physical training only. However, there is a gap in the literature to which extent the addition of IHHE can enhance the effects of an aerobic training. Therefore, the aim of this study was to investigate the efficacy of IHHE applied prior to aerobic cycling exercise on cognitive and physical performance in geriatric patients. Methods: In a randomized, two-armed, controlled, and single-blinded trial, 25 geriatric patients (77-94 years) were assigned to two groups: intervention group (IG) and sham control group (CG). Both groups completed 6 weeks of aerobic training using a motorized cycle ergometer, three times a week for 20 min per day. The IG was additionally exposed to intermittent hypoxic and hyperoxic periods for 30 min prior to exercise. The CG followed the similar procedure breathing sham hypoxia and hyperoxia (i.e., normoxia). Within 1 week before and after the interventions, cognitive performance was assessed with the Dementia-Detection Test (DemTect) and the Clock Drawing Test (CDT), while physical performance was measured using the Timed \"Up and Go\" Test (TUG) and the Short-Physical-Performance-Battery (SPPB). Results: No interaction effect was found with respect to the DemTect (η p 2 = 0.02). An interaction effect with medium effect size (η p 2 = 0.08) was found for CDT performance with a higher change over time for IG (d = 0.57) compared to CG (d = 0.05). The ANCOVA with baseline-adjustment indicated between-group differences with a large and medium effect size at post-test for the TUG (η p 2 = 0.29) and SPPB (η p 2 = 0.06) performance, respectively, in favour of the IG. Within-group post-hoc analysis showed that the TUG performance was worsened in the CG (d = 0.65) and remained unchanged in the IG (d = 0.19). Furthermore, SPPB performance was increased (d = 0.58) in IG, but no relevant change over time was found for CG (d = 0.00). Conclusion: The current study suggests that an additional IHHE prior to aerobic cycling exercise seems to be more effective to increase global cognitive functions as well as physical performance and to preserve functional mobility in geriatric patients in comparison to aerobic exercise alone after a 6-week intervention period.

BACKGROUND: Intermittent hypoxia applied at rest or in combination with exercise promotes multiple beneficial adaptations with regard to performance and health in humans. It was hypothesized that replacing normoxia by moderate hyperoxia can increase the adaptive response to the intermittent hypoxic stimulus.
OBJECTIVE: Our objective was to systematically review the current state of the literature on the effects of chronic intermittent hypoxia-hyperoxia (IHH) on performance- and health-related outcomes in humans.
METHODS: PubMed, Web of Science™, Scopus, and Cochrane Library databases were searched in accordance with PRISMA guidelines (January 2000 to September 2021) using the following inclusion criteria: (1) original research articles involving humans, (2) investigation of the chronic effect of IHH, (3) inclusion of a control group being not exposed to IHH, and (4) articles published in peer-reviewed journals written in English.
RESULTS: Of 1085 articles initially found, eight studies were included. IHH was solely performed at rest in different populations including geriatric patients (n = 1), older patients with cardiovascular (n = 3) and metabolic disease (n = 2) or cognitive impairment (n = 1), and young athletes with overtraining syndrome (n = 1). The included studies confirmed the beneficial effects of chronic exposure to IHH, showing improvements in exercise tolerance, peak oxygen uptake, and global cognitive functions, as well as lowered blood glucose levels. A trend was discernible that chronic exposure to IHH can trigger a reduction in systolic and diastolic blood pressure. The evidence of whether IHH exerts beneficial effects on blood lipid levels and haematological parameters is currently inconclusive. A meta-analysis was not possible because the reviewed studies had a considerable heterogeneity concerning the investigated populations and outcome parameters.
CONCLUSIONS: Based on the published literature, it can be suggested that chronic exposure to IHH might be a promising non-pharmacological intervention strategy for improving peak oxygen consumption, exercise tolerance, and cognitive performance as well as reducing blood glucose levels, and systolic and diastolic blood pressure in older patients with cardiovascular and metabolic diseases or cognitive impairment. However, further randomized controlled trials with adequate sample sizes are needed to confirm and extend the evidence. This systematic review was registered on the international prospective register of systematic reviews (PROSPERO-ID: CRD42021281248) ( https://www.crd.york.ac.uk/prospero/ ).

Epigenetic stimuli induce beneficial or detrimental changes in gene expression, and consequently, phenotype. Some of these phenotypes can manifest across the lifespan-and even in subsequent generations. Here, we used a mouse model of vascular cognitive impairment and dementia (VCID) to determine whether epigenetically induced resilience to specific dementia-related phenotypes is heritable by first-generation progeny.
Our systemic epigenetic therapy consisted of 2 months of repetitive hypoxic \"conditioning\" (RHC) prior to chronic cerebral hypoperfusion in adult C57BL/6J mice. Resultant changes in object recognition memory and hippocampal long-term potentiation (LTP) were assessed 3 and 4 months later, respectively.
Hypoperfusion-induced memory/plasticity deficits were abrogated by RHC. Moreover, similarly robust dementia resilience was documented in untreated cerebral hypoperfused animals derived from RHC-treated parents.
Our results in experimental VCID underscore the efficacy of epigenetics-based treatments to prevent memory loss, and demonstrate for the first time the heritability of an induced resilience to dementia.

Ischemic stroke is one of the most lethal and severely disabling diseases that seriously affects human health and quality of life. The maintenance of self-renewal and differentiation of neural stem cells are closely related to metabolism. This study aimed to investigate whether hypoxic postconditioning (HPC) could promote neurogenesis after ischemic stroke, and to investigate the role of neuronal stem cell metabolism in HPC-induced neuroprotection. Male C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO), and HPC was performed for 3 h per day. Immunofluorescence staining was used to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 21% O2 or 8% O2. HPC promoted the recovery of neurological function in mice on day 14. HPC promoted neuronal precursor proliferation in the subventricular zone (SVZ) on day 7 and enhanced neuronal precursor migration in the basal ganglia and cortex on day 14. Fatty acid oxidation (FAO) and glycolysis of neural stem cells in the SVZ changed after MCAO with or without HPC. HPC promoted the proliferation of NE-4C stem cells, decreased FAO and increased glycolysis. All these beneficial effects of HPC were ablated by the application of an FAO activator or a glycolysis inhibitor. In conclusion, cerebral ischemia modulated the FAO and glycolysis of neural stem cells. HPC promoted the proliferation and migration of neural stem cells after MCAO, and these effects may be related to the regulation of metabolism, including FAO and glycolysis.

We compared the effects of short-term, perceptually regulated training using interval-walking in hypoxia vs. normoxia on health outcomes in overweight-to-obese individuals. Sixteen adults (body mass index = 33 ± 3 kg·m-2) completed eight interval-walk training sessions (15 × 2 min walking at a rating of perceived exertion of 14 on the 6-20 Borg scale; rest = 2 min) either in hypoxia (FiO2 = 13.0%) or normoxia during two weeks. Treadmill velocity did not differ between conditions or over time (p > 0.05). Heart rate was higher in hypoxia (+10 ± 3%; p = 0.04) during the first session and this was consistent within condition across the training sessions (p > 0.05). Similarly, arterial oxygen saturation was lower in hypoxia than normoxia (83 ± 1% vs. 96 ± 1%, p < 0.05), and did not vary over time (p > 0.05). After training, perceived mood state (+11.8 ± 2.7%, p = 0.06) and exercise self-efficacy (+10.6 ± 4.1%, p = 0.03) improved in both groups. Body mass (p = 0.55), systolic and diastolic blood pressure (p = 0.19 and 0.07, respectively) and distance covered during a 6-min walk test (p = 0.11) did not change from pre- to post-tests. Short term (2-week) perceptually regulated interval-walk training sessions with or without hypoxia had no effect on exercise-related sensations, health markers and functional performance. This mode and duration of hypoxic conditioning does not appear to modify the measured cardiometabolic risk factors or improve exercise tolerance in overweight-to-obese individuals.

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called \"hypoxic conditioning\" to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.