Severe Hypoxic Conditions Research Articles

Near-Infrared-II-Activated Transition Metal(II)-Coordinated Ligand Radical Primes Robust Anticancer Immunity.

Photoactivatable metallodrugs combining tumor cell eradication and immune stimulation hold immense promise for targeted cancer therapy. However, limitations such as oxygen dependence, narrow visible light responsiveness, and poor immunogenicity hinder their efficacy in deep solid tumors with hypoxic and immunosuppressive microenvironments. Herein, we present a novel design strategy for transition metal(II)-coordinated ligand radicals exhibiting intense near-infrared-II (NIR-II) absorption, unique endoplasmic reticulum-targeting capability, and oxygen-independent photothermal performance, effectively addressing these constraints. Proof-of-concept results demonstrate the potent efficacy of our cobalt(II)-coordinated ligand radical (BPDP-Co) in inducing highly immunogenic pyroptosis in tumor cells under both normoxic and severe hypoxic conditions upon 1064 nm laser irradiation. This NIR-II activation triggers the release of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, fueling a robust antitumor immune response. In vivo studies demonstrate that treatment with BPDP-Co/NIR-II significantly inhibited 4T1 tumor growth in BALB/c mice with a high inhibitory rate of 85.7%, highlighting its therapeutic potential in tumor immunotherapy.

Changes in reactive oxygen species and autofluorescence under hypoxia at the hippocampal CA3 area: Role of calcium and zinc influxes

Reactive oxygen species (ROS) have an important role in cellular biology, being involved, in a way that depends on their levels, in cell signaling processes or in oxidative stress, probably associated with neurodegenerative and other diseases. Most of the studies about ROS formation were performed in ischemic conditions, and thus, there is limited knowledge about ROS formation in less severe hypoxic conditions. This study investigates neuronal ROS generation and autofluorescence changes in hypoxic conditions, focusing on the involvement of calcium and zinc. Using hippocampal slices from Wistar rats, ROS production was monitored by the permeant fluorescent indicator H2DCFDA under different oxygenation levels. Moderate hypoxia (40% O2) led to a small ROS increase, while severe hypoxia (0% O2) showed a more pronounced rise. KCl-induced depolarization significantly enhanced ROS formation, particularly under severe hypoxia. Inhibition of NMDA receptors reduced ROS generation without affecting autofluorescence, while chelation of zinc ions decreased ROS production and increased flavin adenine dinucleotide (FAD) autofluorescence. These findings suggest that, in hypoxic conditions, ROS formation is mediated by calcium entry through NMDA receptors and also by zinc influxes. Thus, these ions play a crucial role in oxidative stress, which may be related with neurodegenerative diseases associated with ROS dysregulation.

Dual roles of photosynthetic hydrogel with sustained oxygen generation in promoting cell survival and eradicating anaerobic infection

Tissue engineering offers a promising alternative for oral and maxillofacial tissue defect rehabilitation; however, cells within a sizeable engineered tissue construct after transplantation inevitably face prolonged and severe hypoxic conditions, which may compromise the survivability of the transplanted cells and arouse the concern of anaerobic infection. Microalgae, which can convert carbon dioxide and water into oxygen and glucose through photosynthesis, have been studied as a source of oxygen supply for several biomedical applications, but their promise in orofacial tissue regeneration remains unexplored. Here, we demonstrated that through photosynthetic oxygenation, Chlamydomonas reinhardtii (C. reinhardtii) supported dental pulp stem cell (DPSC) energy production and survival under hypoxia. We developed a multifunctional photosynthetic hydrogel by embedding DPSCs and C. reinhardtii encapsulated alginate microspheres (CAMs) within gelatin methacryloyl hydrogel (GelMA) (CAMs@GelMA). This CAMs@GelMA hydrogel can generate a sustainable and sufficient oxygen supply, reverse intracellular hypoxic status, and enhance the metabolic activity and viability of DPSCs. Furthermore, the CAMs@GelMA hydrogel exhibited selective antibacterial activity against oral anaerobes and remarkable antibiofilm effects on multispecies biofilms by disrupting the hypoxic microenvironment and increasing reactive oxygen species generation. Our work presents an innovative photosynthetic strategy for oral tissue engineering and opens new avenues for addressing other hypoxia-related challenges.

Effect of miR-98/IL-6/STAT3 on Autophagy and Apoptosis of Cardiac Stem Cells Under Hypoxic Conditions In vitro.

The heavy burden of cardiovascular diseases demands innovative therapeutic strategies dealing with cardiomyocyte loss. Cardiac Stem Cells (CSCs) are renewable cells in the myocardium with differentiation and endocrine functions. However, their functions are significantly inhibited in conditions of severe hypoxia or inflammation. The mechanism of hypoxia affecting CSCs is not clear. Interleukin-6 (IL-6) appears active in both hypoxic and inflammatory microenvironments. The aim of this study was to explore whether IL-6 is related to CSC apoptosis and autophagy under severe hypoxia. In this study, rat CSCs were extracted by alternate digestion. The interaction of miR-98 and IL-6 mRNA was detected by the dual luciferase method, and qPCR was applied to confirm the effect of miR-98 on IL-6 expression. The effect of IL-6 on CSC apoptosis was measured by flow cytometry and the effect of IL-6 on CSC autophagy by transmission electron microscopy. The western blot method was applied to detect the effect of IL-6 on the expressions of proteins related to apoptosis and autophagy. ANOVA and Dunnett T3's test were employed in the statistical analysis. When p < 0.05, the difference was significant. Under severe hypoxia conditions, IL-6 increased CSC apoptosis and decreased p-STAT3 expression significantly. CSC apoptosis increased significantly after inhibition of the STAT3 signaling pathway under severe hypoxia. IL-6 could also significantly inhibit CSCs' autophagy and block their autophagy flow under severe hypoxic conditions. Meanwhile, it was confirmed that miR-98 had a binding site on IL-6 mRNA and miR-98 significantly inhibited IL-6 mRNA expression in CSCs under severe hypoxic conditions. miR-98/IL-6/STAT3 has been found to be involved in the regulation of CSCs' apoptosis and autophagy under severe hypoxic conditions and there might be a mutual linkage between CSCs' apoptosis and their autophagy.

Loss of Htr1B Leads to a Failure in the Neonate Autoresuscitation Reflex

Sudden Infant Death Syndrome (SIDS) is the leading cause of death in infants under the age of 1, with an unknown etiology, that takes the lives of 3,400 infants per year in the US alone. Interestingly, SIDS cases show males predominance (60%), however this sexual disparity in is not fully understood. SIDS is believed to follow a triple risk hypothesis model where the infant has an innate vulnerability, is at a critical developmental period, and is challenged with an exogenous stressor. A leading hypothesis indicates many SIDS cases are mechanistically driven by a failure in the autoresuscitation reflex. The autoresuscitation reflex is a series of gasps that occur to revitalize normal cardiorespiratory function when an infant falls into a hypoxic coma, characterized by an apnea and bradycardia, due to severe hypoxic conditions (i.e., rebreathing while sleeping in face down or with the face blocked). Although the cause of failure in the autoresuscitation reflex for SIDS remains unknown, post-mortem studies have found abnormalities related to the central serotonin (5-HT) neurotransmitter system, including several 5-HT receptors (5-HTr’s). Follow up studies in animal models show that 5-HT system perturbations result in a significant survival decrease in neonatal animals during anoxic (3% CO2/balance N2) gas challenges that test the autoresuscitation function, including pharmacological receptor manipulations. Furthermore, adult animal studies report that 5-HT receptor stimulation alters various respiratory parameters (i.e., tidal volume, respiratory rate, gasping). What remains to be understood is the cellular and molecular mechanisms through which 5-HT plays a role in the autoresuscitation reflex and how those mechanism may be disrupted in SIDS. We hypothesize that Htr1B is required for successful autoresuscitation. To test this hypothesis, we utilized an automated closed loop robotic platform for neonate cardio-respiratory measurements ( Looper) to assay P7 Htr1B loss of function mice for their abilities to survive repeated anoxic gas challenges testing the autoresuscitation reflex. Using Looper, we find that the loss of Htr1B decreases survival to repeated anoxic challenges compared to wild type (WT) controls in both male and female mice. Additionally, a subset of male heterozygous Htr1B mice survive fewer challenges compared to WT mice, whereas others survive a similar number of challenges as WT mice; a phenotype not observed in female mice. Our data supports the hypothesis that modulations to the serotonin system via Htr1B is important in eliciting the autoresuscitation response. Future studies aim to investigate additional respiratory parameters from respiratory trace data, in addition to recovery parameters, and functionally mapping out where in the brainstem and what neuronal populations require the expression of this receptor for the autoresuscitation reflex. R01 HL161142. This is the full abstract presented at the American Physiology Summit 2024 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.

Lower glycemia levels in subjects with excessive erythrocytosis during the oral glucose tolerance test living in conditions of severe hypoxia.

Previous studies showed that residents of higher elevations have lower glucose levels. Our objective in this study is to determine the basal and postprandial glucose levels in apparently healthy permanent residents of the miner population center of La Rinconada located 5100 meters (m) above sea level. Forty male permanent residents of the Rinconada miner population center were studied. The oral glucose tolerance test was used to evaluate basal and postprandial glycemia levels at 1, 2, and 3h. The individuals had a mean age of 43.95 ± 8.54years. Basal glycemia in subjects without excessive erythrocytosis (EE) was 73.3 ± 7.9mg/dL, while levels in patients with EE were 57.98 ± 7.38mg/dL. In the postprandial period, at 1h after oral glucose overload, a mean value of 76.35 ± 13.53mg/dL was observed in subjects with EE compared to 94.68 ± 9.98mg/dL in subjects without EE. After 2h, subjects with EE had a glycemia level of 72.91 ± 9.17mg/dL EE compared to 90.73 ± 13.86mg/dL without EE. At 3h, the average glycemia level in subjects with EE was 70.77 ± 8.73mg/dL compared to 87.79 ± 14.16mg/dL in those without EE. These findings suggest that under hypoxic conditions, glycemia levels are lower in both subjects with and without EE, having obtained lower levels in subjects with EE in relation to those with normal values of Hb and Hct. The results of this study indicate that in the conditions of severe hypoxia, blood glucose levels are below the values considered normal for sea level.

Thermal tolerance in an extremophile fish from Mexico is not affected by environmental hypoxia.

The thermal ecology of ectotherm animals has gained considerable attention in the face of human-induced climate change. Particularly in aquatic species, the experimental assessment of critical thermal limits (CTmin and CTmax) may help to predict possible effects of global warming on habitat suitability and ultimately species survival. Here we present data on the thermal limits of two endemic and endangered extremophile fish species, inhabiting a geothermally heated and sulfur-rich spring system in southern Mexico: The sulfur molly (Poecilia sulphuraria) and the widemouth gambusia (Gambusia eurystoma). Besides physiological challenges induced by toxic hydrogen sulfide and related severe hypoxia during the day, water temperatures have been previously reported to exceed those of nearby clearwater streams. We now present temperature data for various locations and years in the sulfur spring complex and conducted laboratory thermal tolerance tests (CTmin and CTmax) both under normoxic and severe hypoxic conditions in both species. Average CTmax limits did not differ between species when dissolved oxygen was present. However, critical temperature (CTmax=43.2°C) in P. sulphuraria did not change when tested under hypoxic conditions, while G. eurystoma on average had a lower CTmax when oxygen was absent. Based on this data we calculated both species' thermal safety margins and used a TDT (thermal death time) model framework to relate our experimental data to observed temperatures in the natural habitat. Our findings suggest that both species live near their thermal limits during the annual dry season and are locally already exposed to temperatures above their critical thermal limits. We discuss these findings in the light of possible physiological adaptions of the sulfur-adapted fish species and the anthropogenic threats for this unique system.

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

The tumor microenvironment is comprised of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

Prospective clinical validation of the Empatica EmbracePlus wristband as a reflective pulse oximeter.

Respiratory diseases such as chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, and COVID-19 may cause a decrease in arterial oxygen saturation (SaO2). The continuous monitoring of oxygen levels may be beneficial for the early detection of hypoxemia and timely intervention. Wearable non-invasive pulse oximetry devices measuring peripheral oxygen saturation (SpO2) have been garnering increasing popularity. However, there is still a strong need for extended and robust clinical validation of such devices, especially to address topical concerns about disparities in performances across racial groups. This prospective clinical validation aimed to assess the accuracy of the reflective pulse oximeter function of the EmbracePlus wristband during a controlled hypoxia study in accordance with the ISO 80601-2-61:2017 standard and the Food & Drug Administration (FDA) guidance. Healthy adult participants were recruited in a controlled desaturation protocol to reproduce mild, moderate, and severe hypoxic conditions with SaO2 ranging from 100% to 70% (ClinicalTrials.gov registration #NCT04964609). The SpO2 level was estimated with an EmbracePlus device placed on the participant's wrist and the reference SaO2 was obtained from blood samples analyzed with a multiwavelength co-oximeter. The controlled hypoxia study yielded 373 conclusive measurements on 15 subjects, including 30% of participants with dark skin pigmentation (V-VI on the Fitzpatrick scale). The accuracy root mean square (Arms) error was found to be 2.4%, within the 3.5% limit recommended by the FDA. A strong positive correlation between the wristband SpO2 and the reference SaO2 was observed (r = 0.96, P < 0.001), and a good concordance was found with Bland-Altman analysis (bias, 0.05%; standard deviation, 1.66; lower limit, -4.7%; and upper limit, 4.8%). Moreover, acceptable accuracy was observed when stratifying data points by skin pigmentation (Arms 2.2% in Fitzpatrick V-VI, 2.5% in Fitzpatrick I-IV), and sex (Arms 1.9% in females, and 2.9% in males). This study demonstrates that the EmbracePlus wristband could be used to assess SpO2 with clinically acceptable accuracy under no-motion and high perfusion conditions for individuals of different ethnicities across the claimed range. This study paves the way for further accuracy evaluations on unhealthy subjects and during prolonged use in ambulatory settings.

Reconciling biogeochemical redox proxies: Tracking variable bottom water oxygenation during OAE-2 using vanadium isotopes

Oceanic Anoxic Event-2 (OAE-2, ∼94 Ma ago) is marked by a significant perturbation to the carbon and nutrient cycles. Despite the general idea of widespread expansion of the oceanic anoxia during OAE-2, various localities likely experienced heterogeneous redox fluctuations throughout the roughly 500-thousand-year-long event. In certain localities, redox-sensitive elements imply persistent anoxic-to-euxinic conditions, notwithstanding paleontological data that indicate short-term hypoxic-to-anoxic oscillations in bottom waters. Such discrepancies likely result from sampling resolution, local proxy sensitivity, and/or time-integration of signals, particularly for severe hypoxic conditions. We applied vanadium (V) isotopes to three well-studied OAE-2 localities in the proto-North Atlantic Basin. Under the relatively stable anoxic-to-euxinic conditions throughout OAE-2 at Well S75 and Site 367, the sedimentary δ51V values present consistent variations analogous to modern anoxic-to-euxinic environments. However, at Site 1258, the sedimentary δ51V values present greater perturbations toward more negative values that are indicative of short-term oxygenation in bottom waters. These negative perturbations of δ51V values covary with the abundances of the low-oxygen-tolerant benthic foraminifers. Together, these data refine the heterogeneous redox fluctuations in individual localities, revealing occasional short-term weak oxygenation under the generally anoxic conditions throughout OAE-2. This study documents the unique utility of V isotopes to track bottom water redox fluctuations, particularly short-term variations from anoxic to mildly oxic conditions that are hard to track with other methods.

Deep-sea paleoenvironmental evolution in the mid-Cretaceous of the Basque Pyrenees based on microfaunal analysis (Armintza section)

The mid-Cretaceous Black Flysch Group and Plentzia Formation constitute two key lithostratigraphic units in the evolution of the Pyrenean rift system but many of their paleoenvironmental characteristics are poorly known. In this work, a microfaunal analysis (planktonic and benthic foraminifera and ostracods) of these two units at the Armintza section has been carried out in order to interpret the paleoenvironmental conditions (paleodepth, oxygen level and water masses) in which they deposited, and to relate them to the contemporary tectono-sedimentary settings. Based on the high proportion of planktonic foraminifera with respect to total foraminifera and the assemblages of benthic foraminifera species, a paleodepth of ∼600 m is estimated for studied units. During syn-rift deposition of the organic-rich Black Flysch Gp. in middle Albian-early Cenomanian times, the relative abundance of planktonic foraminifera and the proportions of different shell morphotypes suggest the presence of a shallow water mass and the stagnation of deeper waters. Moreover, the presence of abundant hypoxia-tolerant benthic foraminifera species and the occurrence of only rare hypoxia-tolerant platycopid ostracods indicate severe hypoxia conditions (<1.5 ml/l) or even anoxia at the seafloor. A noticeable change is recorded at the contact between the Black Flysch Gp. and the Plentzia Fm. (lower-middle Cenomanian transition). During post-rift deposition of the Plentzia Fm. in earliest middle Cenomanian times, developed microfaunal assemblage shows an important increase in benthic foraminifera species, many of which indicate intermediate waters, and dominance of keeled planktonic foraminifera suggesting the end of water stagnation and the inflow of an intermediate water mass. In addition, the presence of hypoxia-tolerant species of ostracods and benthic foraminifera indicates the development of mild hypoxia conditions at the seafloor during this interval.

Abstract 3230: Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation

Abstract Radiation therapy (RT) has been prevalently implemented to treat cancer in clinical settings by inducing DNA damage in tumor cells. However, tumor microenvironmental factors such as severe hypoxic conditions and vascular anomalies attenuate the therapeutic efficacy of RT, thus resulting in unsatisfactory outcomes in solid tumors. Recently, Immune checkpoint blockade (ICB) has improved immune recognition to tumor cells and normalized tumor vasculature to diminish hypoxia in solid tumors. Herein, we suggest that RT combined with ICB synergistically alters tumor microenvironments, thus facilitating the recruitment of cytotoxic immune cells into tumors as well as sensitizing radiation effectiveness. RT in combination with ICB not only normalized tumor vasculature to reduce hypoxia, but also increased anti-tumor effects from immune-mediated toxicity and DNA damage-mediated apoptosis in several solid tumor-bearing mouse models to a greater extent than did either monotreatment of RT or ICB. This study will provide mechanistic insight into synergistic effects conferred by RT and ICB as well as a strong preclinical rationale for combining the two therapeutic modalities in human cancers. Citation Format: Minjeong Kang, DaeYong Lee, Yifan Wang, Betty Kim, Wen Jiang. Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3230.

Integrated transcriptomic and metabolomic analysis of cortical neurons reveals dysregulated lipid metabolism, enhanced glycolysis and activated HIF-1 signaling pathways in acute hypoxia

The brain is the main oxygen-consuming organ and is vulnerable to ischemic shock or insufficient blood perfusion. Brain hypoxia has a persistent and detrimental effect on resident neurons. Previous studies have identified alterations in genes and metabolites in ischemic brain shock by single omics, but the adaptive systems that neurons use to cope with hypoxia remain uncovered. In the present study, we constructed an acute hypoxia model and performed a multi-omics analysis from RNA-sequencing and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics on exploring potentially differentially expressed genes (DEGs) and metabolites (DEMs) in primary cortical neurons under severe acute hypoxic conditions. The TUNEL assay showed acute hypoxia-induced apoptosis in cortical neurons. Omics analysis identified 564 DEGs and 46 DEMs categorized in the Kyoto encyclopedia of genes and genomes (KEGG) database. Integrative pathway analysis highlighted that dysregulated lipid metabolism, enhanced glycolysis, and activated HIF-1 signaling pathways could regulate neuron physiology and pathophysiology under hypoxia. These findings may help us understand the transcriptional and metabolic mechanisms by which cortical neurons respond to hypoxia and identify potential targets for neuron protection.

ВЛИЯНИЕ РАЗВЕДЕНИЯ ЛОБСТЕРОВ В ЗАЛИВЕ СУАН ДАЙ, ПРОВИНЦИИ ФУЙЕН НА СОЦИАЛЬНО-ЭКОНОМИЧЕСКУЮ И ЭКОЛОГИЧЕСКУЮ ОБСТАНОВКУ

Xuan Dai Bay, province Phu Yen has diverse biot and high species richness. This is a favorable condition for the development of aquaculture with high-value farming species such as lobster, cobia, grouper... Based on the history of aquaculture and enviromental conditions, the Provincial People's Committee of province Phu Yen planned to develop Xuan Dai Bay into a key aquaculture area for high-quality seafood (lobster). Research results show that lobster farming operations in the area are very crowded and growing rapidly. Lobster farming has made a significant contribution to the socio-economic development of the area in recent years through larval fishing, fresh food supply, and lobster trade. Lobster farming has clearly changed the face of the countryside, creating many jobs, increasing incomes and improving the lives of people in the area. However, leftover food is dumped directly into the bay, which is one of the causes of environmental pollution. At all sampling stations, the content of total organic carbon in bottom sediments is high. It varies widely between sampling stations and tends to be high in the interior of the bay. The average value is 51.21±11.85%, ranging from 26.68% to 62.12%. These organic substances decompose, causing changes in the structure of sediment particles, reducing the amount of dissolved oxygen in water and sediment and even, under severe hypoxic conditions, promoting a series of anaerobic reactions, creating toxins for living organisms.

Disentangling species-specific krill responses to local oceanography and predator’s biomass: The case of the Humboldt krill and the Peruvian anchovy

Euphausiids (hereafter “krill”) are one of the main components of the pelagic communities of the Humboldt Current System (HCS). Their community dynamics have been well studied in central-southern Chile where upwelling is strongly seasonal, but little is known about the permanent-upwelling area of the HCS, which yields the largest fishery in the world, the Peruvian anchovy. We applied hierarchical generalized additive models with environmental and biological predictors to determine the main drivers of krill abundance, adjusting species-specific functions. We used a time series of 16 bi-annual surveys to study annual, seasonal, and spatial scales of variability of the four numerically dominant taxa: Euphausia mucronata (Humboldt krill), E. eximia, Stylocheiron affine, and Nematoscelis spp. The spatial pattern of the Humboldt krill (the dominant species) proved it is an upwelling-associated species, with higher abundances within 10 km from the coast. The other 3 taxa showed opposite spatial patterns with higher abundances offshore. The main covariates explaining krill abundances were the depth of the upper limit of the oxygen minimum zone (dOMZ) and the mean temperature of the water column. Humboldt krill was negatively correlated to both drivers, and the opposite effect was observed for the other taxa. Although many krill species are metabolically adapted to cope with the severe hypoxic conditions of this system, the Humboldt krill was the only species with higher modeled abundances when dOMZ was shallower. Chlorophyll-a remained high during all sampling periods, and it was an insignificant predictor for all taxa, suggesting food is not a limitation for krill in this highly productive system. The acoustic biomass of the Peruvian anchovy had a negative non-linear effect on the abundances of the Humboldt krill, and higher Humboldt krill abundances were found in areas with no anchovy hotspots. Our results indicate that krill in this system are susceptible to changes in temperature, oxygen, and upwelling conditions. Extreme events (e.g. heatwaves and ENSO events) are expected to increase in frequency and intensity, while climate change scenarios show a potential intensification of upwelling. These conditions could lead to distribution displacements and alter trophic interactions by modifying the distribution and biomass of the predator.

Caveolin-1 suppresses hippocampal neuron apoptosis via the regulation of HIF1α in hypoxia in naked mole-rats.

Naked mole-rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system. The present study aimed to investigate the role of Cav-1 in hypoxia-induced neuronal injury. Western blotting analysis and immunocytochemistry showed that Cav-1 expression was significantly upregulated in NMR hippocampal neurons under 8% O2 conditions for 8 h. Cav-1 alleviates apoptotic neuronal death from hypoxia. Downregulation of Cav-1 by lentiviral vectors suggested damage to NMR hippocampal neurons under hypoxic conditions in vitro and in vivo. Overexpression of Cav-1 by LV-Cav-1 enhanced hypoxic tolerance of NMR hippocampal neurons in vitro and in vivo. Mechanistically, the levels of hypoxia inducible factor-1α (HIF-1α) are also increased under hypoxic conditions. After inhibiting the binding of HIF-1α to hypoxia response elements in the DNA by echinomycin, Cav-1 levels were downregulated significantly. Furthermore, chromatin immunoprecipitation assays showed the direct role of HIF1α in regulating the expression levels of Cav-1 in NMR hippocampal neurons under hypoxic conditions. These findings suggest that Cav-1 plays a critical role in modulating the apoptosis of NMR hippocampal neurons and warrant further studies targeting Cav-1 to treat hypoxia-associated brain diseases.

Perceived Exertion And Dyspnea While Cycling During A Hypoxic And Hyperoxic Placebo

Rating of Perceived Exertion (RPE) is used to subjectively quantify and monitor the perception of physical activity, breathlessness or dyspnea, and leg discomfort (RPElegs) during exercise. However, it is unknown how perceptions of exertion can be influenced by expectation of difficulty. PURPOSE: We asked if the placebo and nocebo effects could alter dyspnea and RPEleg by telling subjects they were receiving different concentrations of oxygen during exercise. We hypothesized that subjects would rate their dyspnea and RPElegs higher when they believed they were breathing hypoxic gas and lower when they believed they were breathing hyperoxic gas relative to room air. METHODS: Thirty healthy, active subjects (19 M, 11 F) with normal pulmonary function participated. Prior to exercise, we read a script to ensure subjects understood hypoxic and hyperoxic gas might make breathing feel more difficult and easier, respectively, but intentionally made no mention about RPEleg. Then during 5-minute submaximal cycling trials (60% peak work rate), we deceived subjects by telling them they were breathing different hypoxic (17% and 15% O2) and hyperoxic (23% O2) gas concentrations, when in fact they breathed room air (21% O2). At the end of each trial, we asked subjects for their dyspnea and RPEleg. RESULTS: Cardiorespiratory variables were similar between the trials, however dyspnea and RPElegs changed in a dose-response manner depending on the O2 concentration participants believed they breathed. When subjects believed they were breathing 15% O2, they significantly increased their dyspnea +0.70 ± 0.2 Borg units (p = 0.03) compared to room air, whereas RPElegs did not significantly change +0.35 ± 0.1 Borg units (p = 0.70). When comparing the most severe hypoxic condition, 15% O2, to the 23% hyperoxic condition, subjects significantly increased their dyspnea +1.05 ± 0.4 Borg units (p = 0.003) but did not significantly change RPElegs + 0.55 ± 0.2 Borg units (p = 0.46). CONCLUSION: We found that dyspnea during exercise is susceptible to expectancy, without any accompanying physiological changes. Given that a single unit in dyspnea is considered a minimal clinically important difference, our findings show that the effect of expectation must be considered when interpreting sensations of breathlessness. Support: NSERC

Effects of chronic hypoxia on growth performance, antioxidant capacity and protein turnover of largemouth bass (Micropterus salmoides)

Fluctuations of dissolved oxygen (DO) frequently lead to a hypoxic condition in aquaculture, and hypoxia exerts tremendously adverse effects on fish. The present study mainly investigated the effects of chronic hypoxia on growth performance, antioxidant capacity and protein turnover of largemouth bass (Micropterus salmoides). The fish were exposed to normoxic (86%–95% DO saturation), mild hypoxic (51%–60% DO saturation) and severe hypoxic (17%–26% DO saturation) conditions for 6 weeks, respectively. Results showed that chronic hypoxia significantly reduced the weight gain rate, specific growth rate and feed intake of largemouth bass. The activities of SOD and CAT in serum, as well as SOD and GPX in muscle, were significantly increased in the severely hypoxic condition. The histological analysis showed that the mean diameter of myofiber was significantly decreased during severe hypoxia. Additionally, the levels of gene and protein revealed that chronic severe hypoxia inhibited protein synthesis by downregulating the HIF-1α/REDD1/mTOR signal pathway and promoted protein degradation by activating the pathways of ubiquitin-proteasome, autophagy-lysosome and calcium proteasome. Overall, this study indicated that chronic hypoxia decreased the growth performance of largemouth bass. Meanwhile, chronic severe hypoxia not only enhanced antioxidant capacity, but also contributed to orient in the balance of protein turnover towards catabolism thus causing muscle atrophy. We suggested that for better growth of fish, the dissolved oxygen concentration should be maintained above 60% DO saturation in aquaculture.

Exploration of Different Hypoxia Patterns and Construction of a Hypoxia-Related Gene Prognostic Index in Colorectal Cancer.

IntroductionImmune checkpoint inhibitor (ICI) therapy has been proven to be a highly efficacious treatment for colorectal adenocarcinoma (COAD). However, it is still unclear how to identify those who might benefit the most from ICI therapy. Hypoxia facilitates the progression of the tumor from different aspects, including proliferation, metabolism, angiogenesis, and migration, and improves resistance to ICI. Therefore, it is essential to conduct a comprehensive understanding of the influences of hypoxia in COAD and identify a biomarker for predicting the benefit of ICI.MethodsAn unsupervised consensus clustering algorithm was used to identify distinct hypoxia-related patterns for COAD patients from TCGA and the GEO cohorts. The ssGSEA algorithm was then used to explore the different biological processes, KEGG pathways, and immune characteristics among distinct hypoxia-related clusters. Some hypoxia-related hub genes were then selected by weighted gene coexpression network analysis (WGCNA). Subsequently, univariate Cox regression analysis, multivariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) regression were utilized to construct a hypoxia-related gene prognostic index (HRGPI). Finally, validation was also conducted for HRGPI in prognostic value, distinguishing hypoxia-related characteristics and benefits of ICI.ResultsWe identified four hypoxia-related clusters and found that different hypoxia response patterns induced different prognoses significantly. Again, we found different hypoxia response patterns presented distinct characteristics of biological processes, signaling pathways, and immune features. Severe hypoxia conditions promoted activation of some cancer-related signaling pathways, including Wnt, Notch, ECM-related pathways, and remodeled the tumor microenvironment of COAD, tending to present as an immune-excluded phenotype. Subsequently, we selected nine genes (ANO1, HOXC6, SLC2A4, VIP, CD1A, STC2, OLFM2, ATP6V1B1, HMCN2) to construct our HRGPI, which has shown an excellent prognostic value. Finally, we found that HRGPI has an advantage in distinguishing immune and molecular characteristics of hypoxia response patterns, and it could also be an excellent predictive indicator for clinical response to ICI therapy.ConclusionDifferent hypoxia response patterns activate different signaling pathways, presenting distinct biological processes and immune features. HRGPI is an independent prognostic factor for COAD patients, and it could also be used as an excellent predictive indicator for clinical response to ICI therapy.

Enzyme-Mediated Alleviation of Peroxide Toxicity in Self-Oxygenating Biomaterials.

Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, generating oxygen using CPO is mediated via the generation of toxic levels of hydrogen peroxide (H2 O2 ). The incorporation of antioxidants, such as catalases, can potentially reduce H2 O2 levels. However, the formulation in which catalases can most effectively scavenge H2 O2 within oxygen generating biomaterials has remained unexplored. In this study, three distinct catalase incorporation methods are compared based on their ability to decrease H2 O2 levels. Specifically, catalase is incorporated within HOGMPs, or absorbed onto HOGMPs, or freely laden into the hydrogel entrapping HOGMPs and compared with control without catalase. Supplementation of free catalase in an HOGMP-laden hydrogel significantly decreases H2 O2 levels reflecting a higher cellular viability and metabolic activity of all the groups. An HOGMP/catalase-laden hydrogel precursor solution containing cells is used as an oxygenating bioink allowing improved viability of printed constructs under severe hypoxic conditions. The combination of HOGMPs with a catalase-laden hydrogel has the potential to decrease peroxide toxicity of oxygen generating tissues.