Levels Of Hypoxia Research Articles

Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition – from blunting to augmenting the HVR – occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 – 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one “typical” pattern for VAH in adult rats.

Biodegradable and switchable near-infrared fluorescent probes for hypoxia detection.

Aims: Among solid tumors, hypoxia is a common characteristic and responsible for chemotherapeutic resistance. Hypoxia-sensitive imaging probes are therefore essential for early tumor detection, growth monitoringand drug-response evaluation. Despite significant efforts, detecting hypoxic oxygen levels remains challenging. Materials & methods: This paper demonstrates the use of an amine-rich carbon dot probe functionalized with an imidazole group that exhibits reversible fluorescence switching in normoxic and hypoxic environments. Results & conclusion: We demonstrate the ability to emit near-infrared light only under hypoxic conditions. The probes are found to be biodegradable in the presence of human digestive enzymes such as lipase. Exvivo tissue imaging experiments revealed promising near-infrared signals even at a depth of 5mm for the probe under exvivo imaging conditions.

Spatiotemporal variations of the oxycline and its response to subduction events in the Arabian Sea

The Arabian Sea is a significant hypoxic region in world’s oceans, characterized by the most extensive oxygen minimum zones (OMZs). Both physical and biological processes can alter the vertical and horizontal distribution of dissolved oxygen within the upper ocean and affect the spatial and temporal distribution of hypoxia within the OMZ. To identify the key physical and biological factors influencing the boundaries of oxycline, we analyzed an extensive dataset collected from the biogeochemical-Argo (BGC-Argo) floats during the period of 2010–2022. In particular, we investigated the impact of physical subduction events on the oxycline. Our results shows that the upper boundary of the oxycline deepened in summer and winter, and seemed to be controlled by the mixed layer depth. In contrast, it was shallower during spring and autumn, mainly regulated by the deep chlorophyll maximum. The lower boundary of the oxycline in the western Arabian Sea was predominantly controlled by regional upwelling and downwelling, as well as Rossby waves in the eastern Arabian Sea. Subduction patches originated from the Arabian Sea High Salinity Water (ASHSW) were observed from the BGC-Argo data, which were found to deepen the lower boundary of the oxycline, and increase the oxygen inventory within the oxycline by 8.3%, leading to a partial decrease in hypoxia levels.

The Effects of the Levels of Hypoxia in the Olfactory Nervous System in Mouse Model.

Intermittent hypoxia (IH) results in low-grade inflammation, sympathetic overactivity, and oxidative stress. However, the specific effects of IH on olfaction have not yet been directly assessed and remain unclear. Therefore, the purpose of this study was to investigate the cytotoxic effects of IH exposure on the mouse olfactory epithelium and the relationship between the concentration of hypoxia and the degree of destruction of the olfactory system. Thirty mice were randomly divided into six groups: control (room air for 4weeks), recovery control (room air for 5weeks), IH 5% oxygen concentration, IH 7% oxygen concentration, recovery 5% hypoxia, and recovery 7% hypoxia groups. Mice in the two hypoxia groups were exposed to 5% and 7% oxygen for 4weeks. Mice in the two recovery groups were exposed to room air for 1week after 4weeks of hypoxia period. Based on, the olfactory marker protein (OMP), Olfr1507, ADCY3, and GNAL were lower, whereas S100b and NGFRAP1 messenger RNA (mRNA) levels were higher in the 5% hypoxia group than those in the control group in the olfactory neuroepithelium. In the brain tissue, the changes in RNA analysis for Olfr 1507, OMP, ADCY, and GNAL mRNA were not typical. However, NeuN and GFAP levels were decreased under 5% hypoxia in the brain tissue. In the recovery state, CNPase, S100b and NeuN levels were increased significantly in both the olfactory neuroepithelium and brain tissue in the 5% hypoxia group. The change in RNA activity in PCR was much higher in the 5% hypoxia group than in the 7% hypoxia group. Our findings suggest that IH damages the olfactory neuroepithelium and brain tissue in mouse model. The activity of olfactory marker genes and neurogenesis in the olfactory neuroepithelium were decreased. The levels of oxygen may be affect changes in the olfactory neuroepithelium. The olfactory ensheathing cell may be a major factor in the recovery of the olfactory neuroepithelium.

Environmental impact of water exchange blocking in a strait – a multidisciplinary study in the Baltic Sea

In this study, we report the environmental impact of water exchange blocking by a 3 km road dam built in 1896 in the shallow Väike Strait, north-eastern Baltic Sea. Using a multidisciplinary measurement campaign and numerical simulations, we show ecological conditions in the strait have considerably altered; the previously free-flowing strait now comprises two bays with separate circulation systems. Water exchange in the area close to the dam has decreased 10–12-fold. Since advection is weakened, exchange with the atmosphere and sediments has a relatively greater role in shaping water characteristics. Consequently, occasional very high sea surface temperature, salinity, and total nitrogen, and strong diurnal cycles in water temperature (>4°C) and dissolved oxygen (>4 mg l−1) were observed near the dam in summer. Oxygen levels are continuously below saturation in winter and concentration occasionally drops to hypoxic levels with ice cover. Nitrogen content in sediments near the dam is 3–4 times higher than in neighboring areas. The dam also modifies sea level, wind wave and suspended matter patterns in the strait. Sediments near the dam show elevated content of hazardous substances likely associated with traffic on the dam road. The phytobenthos community near the dam is dominated by annual green algae, which massively decompose during winter. The dam likely impedes fish migration between suitable feeding and spawning areas, also there have been fish kills caused by rapid fluctuations in sea levels, amplified by dam. The construction of new openings would alleviate negative impacts of the dam.

HighAltitudeOmicsDB, an integrated resource for high-altitude associated genes and proteins, networks and semantic-similarities

Millions of people worldwide visit, live or work in the hypoxic environment encountered at high altitudes and it is important to understand the biomolecular responses to this stress. This would help design mitigation strategies for high altitude illnesses. In spite of a number of studies spanning over 100 years, still the complex mechanisms controlling acclimatization to hypoxia remain largely unknown. To identify potential diagnostic, therapeutic and predictive markers for HA stress, it is important to comprehensively compare and analyse these studies. Towards this goal, HighAltitudeOmicsDB is a unique resource that provides a comprehensive, curated, user-friendly and detailed compilation of various genes/proteins which have been experimentally validated to be associated with various HA conditions, their protein–protein interactions (PPIs) and gene ontology (GO) semantic similarities. For each database entry, HighAltitudeOmicsDB additionally stores the level of regulation (up/down-regulation), fold change, study control group, duration and altitude of exposure, tissue of expression, source organism, level of hypoxia, method of experimental validation, place/country of study, ethnicity, geographical location etc. The database also collates information on disease and drug association, tissue-specific expression level, GO and KEGG pathway associations. The web resource is a unique server platform that offers interactive PPI networks and GO semantic similarity matrices among the interactors.These unique features help to offer mechanistic insights into the disease pathology. Hence, HighAltitudeOmicsDBis a unique platform for researchers working in this area to explore, fetch, compare and analyse HA-associated genes/proteins, their PPI networks, and GO semantic similarities. The database is available at http://www.altitudeomicsdb.in.

The Efficacy of Nanoparticle Delivery to Hypoxic Solid Tumors by ciRGD Co-Administration Depends on Neuropilin-1 and Neutrophil Levels.

The ability to improve nanoparticle delivery to solid tumors is an actively studied domain, where various mechanisms are looked into. In previous work, the authors have looked into nanoparticle size, tumor vessel normalization, and disintegration, and here it is aimed to continue this work by performing an in-depth mechanistic study on the use of ciRGD peptide co-administration. Using a multiparametric approach, it is observed that ciRGD can improve nanoparticle delivery to the tumor itself, but also to tumor cells specifically better than vessel normalization strategies. The effect depends on the level of tumor perfusion, hypoxia, neutrophil levels, and vessel permeability. This work shows that upon characterizing tumors for these parameters, conditions can be selected that can optimally benefit from ciRGD co-administration as a means to improve NP delivery to solid tumors.

Azide-Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy.

Resiquimod (R848) is an immunomodulator causing a severe systemic inflammatory reaction due to low tumor selectivity, thus hindering its use in cancer therapy. Therefore, an azide-masked prodrug (R848-N3 ) of R848 was developed, which was selectively activated to R848 in hypoxic tumors. R848-N3 significantly reduces pro-inflammatory cytokines in treated mice to 1/12 compared to R848 at the same dose. In addition, combretastatin A4 nanoparticles (CA4-NPs) were used to enhance the tumor selectivity of R848-N3 by elevating the level of tumor hypoxia. R848-N3 +CA4-NPs had higher tumor selectivity than the intratumoral injection of R848 at 1h after administration. The concentration of the active R848 in the tumor was 21.45-fold that in the heart. Benefiting from the high tumor selectivity of R848-N3 , R848-N3 +CA4-NPs+anti-PD1 exerted 94.1% tumor suppression and 40.0% tumor cure. Therefore, this work highlighted the potential of azide-masking strategy in the development of tumor-selective prodrugs with reduced toxicity. This article is protected by copyright. All rights reserved.

Decoding the gene subnetworks prioritized in prediction with GLRP in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease is the leading cause of brain dementia, along with which substantial failure of organs and mental issues arise. The abundance of AD related data in the current decade has allowed for much advancement in the field using modern machine learning and deep learning techniques to decrypt pathology. Though diagnostic tools have been modeled over such large expanses of data, the black box problem of decoding the significant biological components contributing to the prediction has been overlooked in the research field.MethodGLRP is a method to decode the final predictions of a deep learning method. Since Graph‐CNN are best suited for using the gene expression data modeled over an established whole human PPI network. The usage of GLRP allows us to build the relevance that we need to interpret how the genes contribute to the prediction based on proven PPI network topology as the basis. From the relevance’s obtained of correctly predicted ROSMAP AD subjects and controls, important genes were extracted to be analyzed for functional annotations and pathway analysis with HPRD PPI.ResultThe graph‐CNN model was able to predict between AD subjects and controls with an AUC of 76.58% and test accuracy of 79.167% while the highest accuracy of machine learning models capped at 75% with an AUC of 72.95% from SVM as seen in Table 1. Having found a threshold of 550 genes to have the highest connected component in graph before noisy genes are added to the network as seen in Fig 1, the average relevance of AD subjects and controls provided us with 214 common genes with 181 genes in the largest connected component as seen in Fig 2.ConclusionAlong with tackling the black box problem of the deep learning model using GLRP which has allowed us to gather the important genes from the network view at a higher efficiency than the machine learning models. The top 214 common genes and the network relating to the negative regulation of organelle organization, hypoxia and oxygen level response, and cellular response to tumor necrosis factors could have potential impact on the pathology of AD and its progression.

Effects of Obesity and Calorie Restriction on Cancer Development.

The risk of malignant tumor development is increasing in the world. Obesity is an established risk factor for various malignancies. There are many metabolic alterations associated with obesity which promote cancerogenesis. Excessive body weight leads to increased levels of estrogens, chronic inflammation and hypoxia, which can play an important role in the development of malignancies. It is proved that calorie restriction can improve the state of patients with various diseases. Decreased calorie uptake influences lipid, carbohydrate and protein metabolism, hormone levels and cell processes. Many investigations have been devoted to the effects of calorie restriction on cancer development in vitro and in vivo. It was revealed that fasting can regulate the activity of the signal cascades including AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), p53, mTOR, insulin/ insulin-like growth factor 1 (IGF1) and JAK-STAT. Up- or down-regulation of the pathways results in the decrease of cancer cell proliferation, migration and survival and the increase of apoptosis and effects of chemotherapy. The aim of this review is to discuss the connection between obesity and cancer development and the mechanisms of calorie restriction influence on cancerogenesis that stress the importance of further research of calorie restriction effects for the inclusion of this approach in clinical practice.

0946 CIRCUL: VALIDATION OF A SMART RING FORM OXIMETER IN INDIVIDUALS WITH DARK SKIN PIGMENT

Abstract Introduction The potential impact of skin pigmentation on the accuracy of oximetric assessment has long been known to be a clinically relevant matter. During the COVID pandemic it became apparent that oximeters may underestimate oxyhemoglobin saturation in darkly pigmented individuals. Validation data for SaO2 is not generally available for the many consumer wearable oximeter devices. Circul® (Bodimetrics Corp, Los Angeles, CA), a wearable oximeter with a form factor of a ring, measures several variables for cardiorespiratory assessment (SpO2, movement, heart rate). We aimed to evaluate the accuracy this device in the measurement of SaO2 compared to a simultaneous values obtained by measurement of SaO2 by arterial blood gases. Methods 24 subjects (8 Black, 16 Non-Black) participated in the validation of the Circul device. In an operating suite they had catheters inserted into their radial arteries. They were administered nitrogen rich air which made them hypoxic in steps to an SaO2 of 70%. Arterial blood was sampled at various levels of hypoxia and simultaneous readings were obtained from the Circul device. We compared SaO2 obtained by Circul vs measurement of ABGs by a medical grade blood gas analyzer. Results There was excellent correlation between SaO2 measured by the ring oximeter and ABGs in both Black (y = 1.0174x - 1.573; R² = 0.9414) and Non-Black (y = 1.0209x - 2.5607; R² = 0.9207) subjects. No significant differences were found in comparing the intercept and slopes of the regressions. At ABG of 70% and 100% the SaO2 measured by the ring was calculated to be 69.6% and 100.2% for the Black subjects and 68.9% and 99.5% for the non-Black subjects. Conclusion Results from this study confirmed that Circul oximetry accuracy seems to be independent of the skin tone. Support (if any)

Three Strategies in Engineering Nanomedicines for Tumor Microenvironment-Enabled Phototherapy.

Canonical phototherapeutics have several limitations, including a lack of tumor selectivity, nondiscriminatory phototoxicity, and tumor hypoxia aggravation. The tumor microenvironment (TME) is characterized by hypoxia, acidic pH, and high levels of H2 O2 , GSH, and proteases. To overcome the shortcomings of canonical phototherapy and achieve optimal theranostic effects with minimal side effects, unique TME characteristics are employed in the development of phototherapeutic nanomedicines. In this review, the effectiveness of three strategies for developing advanced phototherapeutics based on various TME characteristics is examined. The first strategy involves targeted delivery of phototherapeutics to tumors with the assistance of TME-induced nanoparticle disassembly or surface modification. The second strategy involves near-infrared absorption increase-induced phototherapy activation triggered by TME factors. The third strategy involves enhancing therapeutic efficacy by ameliorating TME. The functionalities, working principles, and significance of the three strategies for various applications are highlighted. Finally, possible challenges and future perspectives for further development are discussed.

Proinflammatory indicators and the relevance of echocardiography in children with cystic fibrosis.

As the life expectancy improves in cystic fibrosis, cardiac dysfunction is becoming an important risk factor for morbidity and mortality. Here, the association of cardiac dysfunction with proinflammatory markers and neurohormones between cystic fibrosis patients and healthy children was investigated. Echocardiographic measurements of right and left ventricular morphology and functions together with levels of proinflammatory markers and neurohormones (renin, angiotensin-II, and aldosterone) were obtained and analysed in a study group of 21 cystic fibrosis children aged 5-18 years and compared with age- and gender-matched healthy children. It was shown that patients had significantly higher interleukin-6, C-reactive protein, renin and aldosterone levels (p < 0.05), dilated right ventricles, decreased left ventricle sizes, as well as both right and left ventricular dysfunction. These echocardiographic changes correlated with hypoxia, interleukin-1 α, interleukin-6, C-reactive protein, and aldosterone (p < 0.05) levels. The current study revealed that hypoxia, proinflammatory markers, and neurohormones are major determinants of subclinical changes in ventricular morphology and function. While the right ventricle anatomy was affected by cardiac remodeling, the left ventricle changes were induced by right ventricle dilation and hypoxia. A significant but subclinical systolic and diastolic right ventricle dysfunction in our patients was associated with hypoxia and inflammatory markers. Systolic left ventricle function was affected by hypoxia and neurohormones. Echocardiography is a reliable and non-invasive method that is used safely in cystic fibrosis children for screening and detection of cardiac anatomical and functional changes. Extensive studies are needed to determine the time and frequency of screening and treatment suggestions for such changes.

PET/MRI of hypoxia and vascular function in ER-positive breast cancer: correlations with immunohistochemistry

ObjectivesTo explore the relationship between indices of hypoxia and vascular function from 18F-fluoromisonidazole ([18F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor–positive (ER +) breast cancer.MethodsWomen aged > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [18F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [18F]-FMISO influx rate constant, Ki. Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables.ResultsOf the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [18F]-FMISO Ki associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices.ConclusionHypoxia measured by [18F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer.Key Points• Hypoxia, measured by [18F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer.• Increased CAIX expression was associated with higher levels of hypoxia measured by [18F]-FMISO-PET.• Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas.

The Role of Hypoxia and Cancer Stem Cells in Development of Glioblastoma.

Glioblastoma multiform (GBM) is recognized as the most malignant brain tumor with a high level of hypoxia, containing a small population of glioblastoma stem like cells (GSCs). These GSCs have the capacity of self-renewal, proliferation, invasion and recapitulating the parent tumor, and are major causes of radio-and chemoresistance of GBM. Upregulated expression of hypoxia inducible factors (HIFs) in hypoxia fundamentally contributes to maintenance and progression of GSCs. Therefore, we thoroughly reviewed the currently acknowledged roles of hypoxia-associated GSCs in development of GBM. In detail, we recapitulated general features of GBM, especially GSC-related features, and delineated essential responses resulted from interactions between GSC and hypoxia, including hypoxia-induced signatures, genes and pathways, and hypoxia-regulated metabolic alterations. Five hypothesized GSC niches are discussed and integrated into one comprehensive concept: hypoxic peri-arteriolar niche of GSCs. Autophagy, another protective mechanism against chemotherapy, is also closely related to hypoxia and is a potential therapeutic target for GBM. In addition, potential causes of therapeutic resistance (chemo-, radio-, surgical-, immuno-), and chemotherapeutic agents which can improve the therapeutic effects of chemo-, radio-, or immunotherapy are introduced and discussed. At last, as a potential approach to reverse the hypoxic microenvironment in GBM, hyperbaric oxygen therapy (HBOT) might be an adjuvant therapy to chemo-and radiotherapy after surgery. In conclusion, we focus on demonstrating the important role of hypoxia on development of GBM, especially by affecting the function of GSCs. Important advantages have been made to understand the complicated responses induced by hypoxia in GBM. Further exploration of targeting hypoxia and GSCs can help to develop novel therapeutic strategies to improve the survival of GBM patients.

Orexin facilitates the hypoxic ventilatory response via the activation of corticotropin-releasing hormone neurons that project to the nucleus of the solitary tract

The paraventricular nucleus of the hypothalamus (PVN) contributes significantly to the peripheral chemoreflex-mediated respiratory and sympathetic responses to hypoxia, in part via reciprocal interactions with nucleus of the solitary tract (nTS). Previously we showed that orexin neurons in the perifornical hypothalamus are activated by hypoxia and facilitate the hypoxic ventilatory response (HVR) in the active phase of the circadian cycle . The neural circuitry through which orexin facilitates the HVR is unknown. Orexin receptors (OxR) are expressed in the PVN, and we recently showed that OxR blockade reduced the activation of both corticotropin-releasing hormone neurons in the PVN as well as nTS neurons. In addition, hypoxia activated orexin neurons projecting to the PVN, but not those projecting to nTS. Here we further explored the hypothesis that orexin facilitates the HVR and arterial blood pressure (ABP) response to hypoxia via the activation of nTS-projecting CRH neurons, and that specific OxR1 knockdown in the PVN would reduce the HVR. To test these hypotheses, we nanoinjected fluorescent retrobeads bilaterally into the nTS to label nTS-projecting neurons. Rats were then exposed to hypoxia (2hrs at 11% O2 during the active phase) following injection of either suvorexant (OxR antagonist; 20 mg/kg i.p.; n=4), or vehicle (DMSO; n=4). Using immunohistochemistry (IHC) we then quantified the number of activated (i.e., Fos-immunoreactive; IR) nTS-projecting CRH neurons. In separate groups of rats we nanoinjected shRNA to knockdown Ox1R expression specifically in the PVN (n=8). PVN of control rats was nanoinjected with scrambled RNA (scRNA; n=3) or aCSF (n=2). Three weeks later, rats were exposed to graded hypoxia (from 21% to 10% inspired O2) over 3-5 minutes to assess the acute HVR and ABP response to different levels of hypoxia. OxR blockade reduced the number of Fos-IR, nTS-projecting CRH neurons by ~32% (drug: p&lt;0.0001). Images confirmed successful targeting of shRNA to PVN, and OxR1 knockdown (by ~50%) was confirmed in subsets of samples by Western Blot and IHC. Ox1R knockdown specifically in the PVN had no effect on resting ventilation, but significantly reduced the HVR (main effect: p=0.02; 22% decrease in VE/VCO2 at 13% O2), due to a reduction in the respiratory frequency response to hypoxia (main effect: p=0.004; 38 breath/min decrease at 13% O2). Ox1R knockdown also decreased ABP (~5 mmHg at all O2 levels; main effect: p=0.0015), but not its response to hypoxia. These data suggest that orexin neurons facilitate the HVR via OxR1 Grants: 5R01HL098602 (EH, DK), 5R01HL136710 (KC) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of different levels of acute hypoxia on subsequent oral glucose tolerance in males with overweight: A balanced cross-over pilot feasibility study.

Previous research has shown that ≤60 min hypoxic exposure improves subsequent glycaemic control, but the optimal level of hypoxia is unknown and data are lacking from individuals with overweight. We undertook a cross-over pilot feasibility study investigating the effect of 60-min prior resting exposure to different inspired oxygen fractions (CON FI O2 =0.209; HIGH FI O2 =0.155; VHIGH FI O2 =0.125) on glycaemic control, insulin sensitivity, and oxidative stress during a subsequent oral glucose tolerance test (OGTT) in males with overweight (mean (SD) BMI=27.6 (1.3) kg/m2 ; n=12). Feasibility was defined by exceeding predefined withdrawal criteria for peripheral blood oxygen saturation (SpO2 ), partial pressure of end-tidal oxygen or carbon dioxide and acute mountain sickness (AMS), and dyspnoea symptomology. Hypoxia reduced SpO2 in a stepwise manner (CON=97(1)%; HIGH=91(1)%; VHIGH=81(3)%, p < 0.001), but did not affect peak plasma glucose concentration (CON=7.5(1.8) mmol∙L-1 ; HIGH=7.7(1.1) mmol∙L-1 ; VHIGH=7.7(1.1) mmol∙L-1 ; p=0.777; η2 =0.013), plasma glucose area under the curve, insulin sensitivity, or metabolic clearance rate of glucose (p > 0.05). We observed no between-conditions differences in oxidative stress (p > 0.05), but dyspnoea and AMS symptoms increased in VHIGH (p < 0.05), with one participant meeting the withdrawal criteria. Acute HIGH or VHIGH exposure prior to an OGTT does not influence glucose homeostasis in males with overweight, but VHIGH is associated with adverse symptomology and reduced feasibility.

Decreasing FIO2 induces spontaneous intermittent hypoxic events in mice

Chronic intermittent hypoxia, CIH, is a feature of sleep apnea widely used in research to mechanistically examine the physiological effects of sleep apnea. These mechanistic studies commonly utilize mice as the study model. In room air, mice experience periodic apneas and arterial oxygen desaturations. Activation of the carotid body could stabilize breathing and decrease these events. Therefore, we hypothesized that C57BL/6J mice experience fewer hypoxic events with decreasing F I O 2 .We placed 6 C57BL/6J mice (3 male, 3 female) in an Emka ® unrestrained barometric plethysmograph and measured pulse oximetry using the STARR LifeSciences MouseOx ® Plus system. The mice were exposed to different levels of F I O 2 for 10 minutes each: 0.21, 0.15, 0.12, 0.09, 0.30 ± 0.01. We defined a hypoxic event as 3% deviation from the average oxygen saturation at each F I O 2 . Mice did not show fewer hypoxic events when exposed to increasing levels of hypoxia. In fact, mice experienced more hypoxic events at 0.15 than 0.21 and 0.30 F I O 2 (P&lt;0.05). Mice also experienced more hypoxic events at 0.12 than at 0.30 F I O 2 . Additionally, we found that hypoxic event nadir SpO 2 was significantly lower at all F I O 2 levels when compared to 0.21 F I O 2 . Hypoxic events at all F I O 2 levels had significantly lower average SpO 2 compared to 0.21 F I O 2 . No change was observed for average SpO 2 for hypoxic events at 0.30 F I O 2 relative to 0.21 F I O 2 . Contrary to our hypothesis, intermittent hypoxic events are not stabilized by exposure to a hypoxic environment. Future work will evaluate this in other mouse strains. 1R56HL152365 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypoxic ventilatory response and respiratory chemosensitivity in differing rat models of female sex hormone loss

Respiratory function is modulated by circulating sex steroids. Specifically, concentrations of circulating 17β-estradiol and progesterone regulate the responsiveness of the respiratory system in adult female rats. Progesterone was first noted to influence breathing following the observation that pregnancy impacted blood gasses. 17β-estradiol is the most abundant and neuroactive form of estrogen, and female respiratory neuroplasticity is dependent on its presence. Circulating sex hormone levels fluctuate across the normal estrus cycle and gradually decline as part of the natural aging process. The specific influences of sex hormones on hypoxic ventilatory response (HVR) and chemosensitivity are slowly emerging in the literature. A developing pattern is that short-term hormone fluctuations, such as estrus cycle, do not appear to significantly change basic respiratory responsiveness. However, less is known about larger hormone shifts, such as those following the loss of gonads or with natural aging. We hypothesized that the loss of sex hormones would differentially impact HVR and chemosensitivity in an ovariectomy (OVX) model versus a naturally aged female rat. Specifically, we theorized that aged rats would demonstrate reduced sensitivity to hypoxia and reduced dynamic range within ventilatory output, as compared to OVX and intact female rats. Three experimental groups of female rats were used: young rats (3 mos old; n=4), young OVX rats (n=5), and aged rats (&gt;24 mos old; n=5). Chemosensitivity was measured during progressive hypoxic challenges at 15%, 12%, and 9% oxygen (O 2 ) using unrestrained barometric plethysmography. Serum samples were taken for measurement of estrogen (E 2 ) and progesterone (P) using ELISA assays. At the highest level of hypoxia (9% O 2 ), all groups exhibited intact chemosensitivity as demonstrated by significant changes in minute ventilation (V E ; &lt; 0.05), V E controlling for metabolism (V E / VCO 2 ; &lt; 0.05), and respiratory neural drive (calculated as the ratio of tidal volume (T V ) to inspiratory time (Ti), controlling for metabolism; T V /T i /VCO 2 ; &lt; 0.05). Further analysis showed that young and OVX groups demonstrated greater sensitivity to hypoxia as compared to the aged group. Using analyses targeting rate of change, the young and OVX groups had a faster rate of change in V E , V E / VCO 2 , and T V /T i /VCO 2 (&lt; 0.05) as the hypoxia intensity increased. ELISA analyses suggest that E 2 , but not P, concentration is significantly correlated with these results (&lt; 0.05). Collectively, these data indicate that aging impacts respiratory function in complex and unique ways that differ from OVX in female rats. This may be significant since OVX is commonly used as a model of age-related physiological changes. University of Minnesota BIRCWH/Women's Health Research Program Seed Grant, National Heart Lungs Brain Institute R01HL146477, Rehabilitation Science Graduate Program, UMN Medical School This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cupric-ion-promoted fabrication of oxygen-replenishing nanotherapeutics for synergistic chemo and photodynamic therapy against tumor hypoxia.

Mixing a glutathione (GSH)-responsive carboxy zinc(II) phthalocyanine (ZnPc*) and CuSO4·5H2O in water with or without the presence of the anticancer drug SN38 resulted in the formation of self-assembled nanotherapeutics labeled as ZnPc*/Cu/SN38@NP and ZnPc*/Cu@NP, respectively. The Cu2+ ions not only promoted the self-assembly of the carboxy phthalocyanine through metal complexation, but also catalyzed the transformation of H2O2 to oxygen via a catalase-like reaction, rendering an oxygen-replenishing property to the nanosystems. Both nanosystems exhibited high stability in aqueous media, but the nanoparticles disassembled gradually in an acidic or GSH-enriched environment and inside human colorectal adenocarcinoma HT29 cells, releasing the encapsulated therapeutic components. The disassembly process together with the activation by the intracellular GSH led to relaxation of the intrinsic quenching of the nanophotosensitizers and restoration of the photoactivities of ZnPc*. Under a hypoxic condition, ZnPc*/Cu/SN38@NP could attenuate the intracellular hypoxia level and maintain the photodynamic activity due to its Cu2+-promoted oxygen-replenishing ability. The photodynamic effect of ZnPc* and the anticancer effect of SN38 worked cooperatively, causing substantial apoptotic cell death. The dual therapeutic actions could also effectively inhibit the tumor growth in HT29 tumor-bearing nude mice without initiating notable adverse effects to the mice. STATEMENT OF SIGNIFICANCE: The oxygen-dependent nature of photodynamic therapy generally reduces its efficacy against tumor hypoxia, which is a common characteristic of advanced solid tumors and usually leads to resistance toward various anticancer therapies. We report herein a facile approach to assemble a glutathione-responsive carboxy phthalocyanine-based photosensitizer and an anticancer drug in aqueous media, in which Cu(II) ions were used to promote the self-assembly through metal complexation and catalyze the conversion of H2O2 to oxygen through a catalase-like reaction, making the resulting nanoparticles possessing an oxygen-replenishing property that could promote the photodynamic effect against hypoxic cancer cells and tumors. The use of Cu(II) ions to achieve the aforementioned dual functions in the fabrication of advanced nano-photosensitizing systems has not been reported.