Normal Oxygen Supply Research Articles

New Insights into the Mechanism by Which the Pituitary Gland Copes with Hypoxia Stress Based on a Transcriptomic Analysis of Megalobrama amblycephala.

Hypoxia is a common environmental stressor in aquatic ecosystems, and during the cultivation process, Megalobrama amblycephala is prone to death because it is hypoxia-intolerant, which brings huge economic losses to farmers. The pituitary gland is a crucial endocrine gland in fish, and it is mainly involved in the secretion, storage, and regulation of hormones. In the present study, we compared the transcriptional responses to serious hypoxia in the pituitary gland among hypoxia-sensitive (HS) and hypoxia-tolerant (HT) M. amblycephala and a control group that received a normal oxygen supply (C0). The fish were categorized according to the time required to lose balance during a hypoxia treatment. A total of 129,251,170 raw reads were obtained. After raw sequence filtering, 43,461,745, 42,609,567, and 42,730,282 clean reads were obtained for the HS, HT, and C0 groups, respectively. A transcriptomic comparison revealed 1234 genes that were differentially expressed in C0 vs. HS, while 1646 differentially expressed genes were obtained for C0 vs. HT. In addition, the results for HS vs. HT showed that 367 upregulated and 41 downregulated differentially expressed genes were obtained for a total of 408 differentially expressed genes. A KEGG analysis of C0 vs. HS, C0 vs. HT, and HS vs. HT identified 315, 322, and 219 enriched pathways, respectively. Similar hypoxia-induced transcription patterns suggested that the downregulated DEGs and enriched pathways were related to pathways of neurodegeneration in multiple diseases, pathways in cancer, thermogenesis, microRNAs in cancer, diabetic cardiomyopathy, and renin secretion. However, in the upregulated DEGs, the PI3K-Akt signaling pathway (C0 vs. HS), microRNAs in cancer (C0 vs. HT), and HIF-1 signaling pathway (HS vs. HT) were significantly enriched. There is a lack of clarity regarding the role of the pituitary gland in hypoxic stress. These results not only provide new insights into the mechanism by which pituitary tissue copes with hypoxia stress in M. amblycephala but also offer a basis for breeding M. amblycephala with hypoxia-resistant traits.

Annexin-A5 monomer as a membrane repair agent for the treatment of renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is one of the causes of acute kidney injury. Annexin A5 (AnxA5), a calcium-dependent cell membrane-binding protein, shows protective effects in various organ IRI models. This study explored the therapeutic effect of exogenous AnxA5 monomer protein on renal IRI and its potential mechanism of action. Different doses of AnxA5 were injected intravenously to treat bilateral renal IRI in SD rats. This model confirmed the protective effects of AnxA5 on kidney structure and function. In vitro, HK-2 cells were subjected to hypoxia for 12h, followed by restoration of normal oxygen supply to simulate IRI. In vitro experiments demonstrated the mechanism of action of AnxA5 by measuring cellular activity and permeability. A comparison of the mutant AnxA5 protein M23 and the application of a calcium-free culture medium further validated the protective effect of AnxA5 by forming a network structure. Exogenous AnxA5 monomers prevented renal IRI by binding to the damaged renal tubular epithelial cell membrane, forming a two-dimensional network structure to maintain cell membrane integrity, and ultimately prevent cell death.

Protective effect of oral stem cells extracellular vesicles on cardiomyocytes in hypoxia-reperfusion.

Hypoxia signaling plays an important role in physiological and pathological conditions. Hypoxia in the heart tissue can produce different consequences depending on the duration of exposure to the hypoxic state. While acute hypoxic exposure leads to a reversible acclimatization in heart tissue with normal systemic oxygen supply, chronic hypoxia exacerbates cardiac dysfunction, leads to a destruction of the tissue. Extracellular vesicles (EVs) are small membrane vesicles that act as mediators of intercellular communication. EVs are secreted by different cell types and those produced by oral cavity-derived mesenchymal stem cells (MSCs), including human gingival MSCs (hGMSCs), have pro-angiogenic and anti-inflammatory effects and showed therapeutic role in tissue regeneration. The aim of the present work was to evaluate the potential protective and regenerative role of EVs produced by hGMSCs, in an in vitro model of hypoxia-conditioned HL-1 cardiomyocytes through the expression analysis of following inflammatory, oxidative stress, angiogenesis, cell survival and apoptotic markers: HIF-1α, P300, NFkB, CCL2, IL1B, IL6, NRF2, CASP-3, BAX and VEGF. Results showed that hGMSCs-derived EVs exerted protection HL-1 cardiomyocytes exposed to both pre and post hypoxic conditions. Moreover, modulation of CASP3 and BAX expression demonstrated that EVs reduced the apoptosis. The analysis of microRNAs in EVs derived from hGMSCs was performed to assess the epigenetic regulation of the presented markers. The following microRNAs: hsa-miR-138-5p, hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-21-5p, hsa-miR-324-5p, hsa-miR-133a-3p, hsa-miR-150-5p, hsa-miR-199a-5p, hsa-miR-128-3p and hsa-miR-221-3p can directly or indirectly target the studied genes by determining their modulation obtained in our study. The data from this study suggested that EVs obtained from hGMSCs may be considered for the cell free treatment option in hypoxia-driven cardiac tissue dysfunction.

Influence of oxygen uptake through the liver surface on the metabolism of ex vivo perfused liver during hypoxia

The low quality of transplants having undergone hypoxic injury can lead to postoperative complications. The aim of the present research is to estimate, by means of mathematical modeling, how the process of oxygen uptake through the liver surface influences the metabolism of ex vivo perfused liver under hypoxia. The value of oxygen uptake through the surface was established to depend on the degree of oxygenation of the perfusion medium. A decrease in the oxygenation of the perfusion medium resulted in a decreased oxygen uptake through the liver surface. Stoichiometric modeling of the liver metabolism shows that upon the decreased oxygenation of the perfusion medium more energy is required for the process of oxygen uptake through the surface even at a lower level as compared to the normal oxygen supply. The application of the Pareto optimality allows estimating the optimum distribution of the energy resources in liver under ex vivo conditions. Both upon the normal and decreased oxygenation of the perfusion medium, the phenomenon of “free competition” for the resource was observed, with the energy being optimally distributed among all the metabolic fluxes. Moreover, this energy is also spent on the accompanying processes, e.g. for the transport of interstitial fluid.

Adaptive potential of the Mediterranean mussel Mytilus galloprovincialis to short-term environmental hypoxia

Environmental hypoxia naturally occurs in coastal ecosystems and bivalve mollusks have to frequently face fluctuations of dissolved oxygen concentrations. Exposure to hypoxia is often associated with the change of the antioxidant and functional status in bivalves, and restoration of the normal oxygen supply is considered to induce oxidative stress in tissues of mollusks. The study investigates changes in the activity of two antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), as well as the expression level of SOD and CAT genes in gills of the Mediterranean mussel, Mytilus galloprovincialis, under exposure to low dissolved oxygen concentration (2.2 mg L−1) for 24 h and 72 h, and 24 h reoxygenation period. We also evaluated the intracellular level of reactive oxygen species (ROS), mortality and changes in mitochondrial membrane potential in hemocytes following hypoxia-reoxygenation cycle. 24 h exposure to hypoxia significantly decreased activity of both enzymes, which then recovered up to control levels at the end of 72 h experimental period for SOD and after reoxygenation for CAT. Expression of antioxidant enzyme genes was up-regulated following the 72 h hypoxic exposure period and returned to the basal normoxic level after 24 h reoxygenation. Hypoxia demonstrated a time-dependent effect on the functional state of hemocytes. The 24 h exposure period did not influence aerobic respiration of hemocytes, but prolonged hypoxia (72 h) was associated with a substantial decrease in mitochondrial membrane potential of hemocytes. The intracellular ROS level and mortality of hemocytes did not change under hypoxia. Reoxygenation period was accompanied with a significant decrease of intracellular ROS level. This study indicated that hypoxia did not induce the pronounced oxidative stress in gills and the changes in the antioxidant status were reversible within 24 h of reoxygenation. Hemolymph demonstrated a stable functional state indicating the tolerance of mussels to short-time hypoxia.

Goal-directed therapy based on rScO2 monitoring in elderly patients with one-lung ventilation: a randomized trial on perioperative inflammation and postoperative delirium

BackgroundThe incidence of postoperative delirium (POD) is high in elderly patients with one-lung ventilation, which is mostly related to the impairment of cerebral oxygen supply/demand balance during operation. (Surgical) stress can cause changes to normal physiological function and increase oxygen supply to the brain. When cerebral oxygen supply/demand is unbalanced, other organs may have already suffered from hypoperfusion or even hypoxic damages leading to increased release of inflammatory factors. Regional saturation of cerebral oxygenation (rScO2) monitoring can noninvasively monitor the variation of regional cerebral oxygen supply/demand balance in real time, and it has a good correlation with the occurrence of POD. S-100β is one of the markers commonly used to predict and diagnose POD, and lactate is one of the important indicators for the quality of tissue perfusion. The study explores whether the goal-directed therapy based on rScO2 monitoring can reduce perioperative inflammatory factor levels and POD incidence in elderly patients with one-lung ventilation and improve tissue perfusion.MethodsThe study is registered on Chinese Clinical Trial Registry (ChiCTR2100054888). A total of 159 patients scheduled for thoracoscopic lobectomy under general anesthesia were divided into the control group (n = 81) and the goal-directed therapy group (GDT group, n = 78). On the basis of the conventional management in the control group, the GDT group applied goal-directed rScO2 monitoring to maintain rScO2 at ±20% baseline level during one-lung ventilation. The levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, and lactate; the intensity of postoperative pain; and the incidence of POD before anesthesia (T1), at the end of operation (T2), on day 1 after operation (T3), on day 3 after operation (T4), and on day 7 after operation or before discharge (T5) were compared respectively between the two groups.ResultsThe incidence of POD at T3 and the awakening time in the GDT group were lower than those in the control group (P < 0.05). During T2 to T4, the levels of inflammatory factors and lactate concentration in the control group were higher than those in the GDT group (P < 0.05). During T3 to T4, the levels of C-reactive protein and lactate in the control group were higher than those in the GDT group (P < 0.05). During T2 to T3, the levels of S-100β in the control group were higher than those in the GDT group (P < 0.05). The levels of inflammatory factors and lactate concentration in both groups during T2 to T4 were higher than those at T1 and T5 (P < 0.05), and there was no statistical difference at T1 versus T5 (P > 0.05). There was no significant difference in postoperative pain intensity, the incidence of agitation during awakening, and postoperative hospital stays between the two groups.ConclusionGoal-directed therapy based on rScO2 monitoring can reduce perioperative inflammatory factor levels, postoperative delirium incidence, and postoperative awakening time and improve tissue perfusion in elderly patients with one-lung ventilation.Trial registrationThe Chinese Clinical Trial Registry ChiCTR2100054888. Registered on 28 December 2021

Effect of doxofylline on pulmonary inflammatory response and oxidative stress during mechanical ventilation in rats with COPD

ObjectiveTo evaluate the effects of doxofylline on inflammatory responses and oxidative stress during mechanical ventilation in rats with chronic obstructive pulmonary disease (COPD).MethodsEight-week-old male Sprague Dawley rats were selected, and the COPD rat model was constructed. The rats were randomly divided into a model group (group M), a model + normal saline group (group N), a doxofylline group (group D), and a control group fed with conventional chow and given normal oxygen supply (group C) (n = 12 in each group). Tracheal intubation and mechanical ventilation were conducted in the rats in each group after anesthesia. A real-time intravenous infusion with 50 mg/kg of doxofylline was conducted in group D, and there was no drug intervention in groups C, N and M. Pathological manifestations of the pulmonary tissues were observed and compared among the groups. And some indicators were evaluated.Results(1) The pulmonary tissues of the rats in groups M, N, and D exhibited typical pathological histological changes of COPD. (2) Groups M, N, and D showed increased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue and BALF, and decreased PaO2 and IL-10 and SOD levels, compared with group C. (3). Group D showed decreased Ppeak, PaCO2, total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue, and increased PaO2 and IL-10 and SOD levels, compared with group N or M.ConclusionDoxofylline was shown to improve ventilation and air exchange during mechanical ventilation in rats with COPD, reduce the inflammatory response and oxidative stress, and mitigate the degree of pulmonary tissue injury.

Abstract NT-102: CHEMICALLY INDUCED HYPOXIA PROMOTES OVARIAN CANCER CHEMORESISTANCE

Abstract The accumulation of cells, derived from the imbalance between the aberrant proliferation and resistance to apoptosis of cancer cells, leads to an increased consumption and consequently decreased availability of oxygen (hypoxia). Hypoxia Inducible Factor (HIF-1) is the key regulator of cell adaptive response under different extracellular stimuli. Subunit HIF-1α is kept at low levels under normal oxygen supply, but strongly upregulated under hypoxia. HIF-1α is overexpressed in several malignant and metastatic tumors but its significance in ovarian cancer prognosis is still controversial. CoCl2 is a chemical compound widely used as a positive control for the upregulation of HIF-1α by preventing its proteosomal degradation. Acquired chemoresistance is considered one of the main factors associated with poor prognosis and survival in ovarian cancer patients, and therefore, its understanding is nowadays one of the major challenges pursued to facilitate treatment and increase life expectation of patients. The aim of this study was to determine the possible role of HIF-1α in the development of chemoresistance in ovarian carcinoma. A27801A9 ovarian cancer cell line was treated with 100 μM CoCl2 for 3, 6 12 and 22 hours for chemical induction of hypoxia. Response to cisplatin and paclitaxel chemotherapeutic drugs was tested and compared with untreated cells (normoxia). Western blot was used to test epithelial-to-mesenchymal transition (EMT) and lysyl oxidase (LOx) markers, and enzyme-linked immunosorbent assay (ELISA) to test the secretion of cytokines in cell supernatant. Chemical hypoxia resulted in paclitaxel resistance in a dose-dependent manner, with 7 to 19% increased viability for hypoxic cells in relation to normoxic cells. No effect was observed for cisplatin. HIF-1α expression achieved the maximum level at 12 hours. Mesenchymal markers N-cadherin and vimentin, as well as the transcription factor snail were not remarkably affected, while epithelial marker E-Cadherin expression was reduced at 22 hours and transcription factor slug presented the maximum expression at 12 hours, as well as lysyl oxidase. Tumor necrosis factor (TNF-α) was not affected by the treatments, while inflammatory interlukins IL-6, IL-10 and IL-1β showed differentiated responses, with a slight increase of 3 pg/mL of IL-10 at 12 hours, a decrease of IL-6 in a time dependent manner (from 40 to 3 pg/mL), and a decreased secretion of IL-1β (around 50%) in relation to the control for all the treatment times. These results suggest that epithelial morphology may begin to be lost at 12 hours, through downregulation of E-cadherin mediated by slug as a consequence of HIF-1α upregulation. In addition, the differential expression of cytokines suggests that HIF-1α may be involved in the cellular immune adaptive response. The enhanced mitotic capacity that has been associated to LOx, was possibly increased due to HIF-1α upregulation, reducing the effectivity of paclitaxel and contributing to a consequent acquired chemoresistance. Citation Format: Andrea Nieto-Veloza, Qixin Zhong, Vermont P Dia. CHEMICALLY INDUCED HYPOXIA PROMOTES OVARIAN CANCER CHEMORESISTANCE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-102.

Mitochondrial dysfunction and role in spreading depolarization and seizure.

The effect of pathological phenomena such as epileptic seizures and spreading depolarization (SD) on mitochondria and the potential feedback of mitochondrial dysfunction into the dynamics of those phenomena are complex and difficult to study experimentally due to the simultaneous changes in many variables governing neuronal behavior. By combining a model that accounts for a wide range of neuronal behaviors including seizures, normoxic SD, and hypoxic SD (HSD), together with a detailed model of mitochondrial function and intracellular Ca2+ dynamics, we investigate mitochondrial dysfunction and its potential role in recovery of the neuron from seizures, HSD, and SD. Our results demonstrate that HSD leads to the collapse of mitochondrial membrane potential and cellular ATP levels that recover only when normal oxygen supply is restored. Mitochondrial organic phosphate and pH gradients determine the strength of the depolarization block during HSD and SD, how quickly the cell enters the depolarization block when the oxygen supply is disrupted or potassium in the bath solution is raised beyond the physiological value, and how fast the cell recovers from SD and HSD when normal potassium concentration and oxygen supply are restored. Although not as dramatic as phosphate and pH gradients, mitochondrial Ca2+ uptake has a similar effect on neuronal behavior during these conditions.

Transcriptome and gene expression analysis of docosahexaenoic acid producer Schizochytrium sp. under different oxygen supply conditions

BackgroundSchizochytrium sp. is a promising strain for the production of docosahexaenoic acid (DHA)-rich oil and biodiesel, and has been widely used in the food additive and bioenergy industries. Oxygen is a particularly important environmental factor for cell growth and DHA synthesis. In general, higher oxygen supply favors lipid accumulation, but could lead to a reduction of the DHA percentage in total fatty acids in Schizochytrium sp. To tackle this problem, it is essential to understand the mechanisms regulating the response of Schizochytrium sp. to oxygen. In this study, we aimed to explore the acclimatization of this DHA producer to different oxygen supply conditions by examining the transcriptome changes.ResultsTwo different fermentation processes, namely normal oxygen supply condition (shift agitation speeds from 400 rpm to 300 rpm) and high oxygen supply condition (constant agitation speeds: 400 rpm), were designed to study how the fermentation characteristics of Schizochytrium sp. HX-308 were affected by different oxygen supply conditions. The results indicated that high oxygen supply condition resulted in 49% and 37.5% improvement in the maximum cell dry weight (CDW) and total lipid concentration, respectively. However, the DHA percentage in total fatty acids decreased to 35%, which was 31.4% lower than that produced by normal oxygen supply condition. Moreover, transcriptome analysis was performed to explore the effect of the oxygen supply condition on genetic expression and metabolism. The results showed that glycolysis and pentose phosphate pathway metabolism-associated genes (hexokinase, phosphofructokinase, fructose-bisphosphate aldolase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase) were substantially upregulated in response to high oxygen supply, resulting in more NADPH was available for Schizochytrium. Specially, high oxygen supply condition also led to genes (Δ6 desaturase, Δ12 desaturase, FAS, ORFA, ORFB, and ORFC) involved in fatty acid biosynthesis upregulation. In addition, a transcriptional upregulation of catalase (CAT) became apparent under high oxygen supply condition, while superoxide dismutase (SOD) and ascorbate peroxidase (APX) were found to be down-regulated.ConclusionsThis study is the first to investigate the differences of gene expression at different levels of oxygen availability in the DHA producer Schizochytrium. The results of transcriptome analyses indicated that high oxygen supply condition resulting in more NADPH and acetyl-CoA production for cell growth and lipid synthesis in Schizochytrium. Δ12 desaturase and ORFC showed higher expression levels at high oxygen supply condition, which might be the key regulators for enhancing fatty acid biosynthesis in the future. These results enrich the current knowledge regarding genetic expression and provide important information to enhance DHA production in Schizochytrium sp.

Retinal Vascular Degeneration in the Transgenic P23H Rat Model of Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases involving a progressive degeneration of photoreceptor cells. Following the loss of photoreceptors, retinal vascularization tends to decrease, which seems to play a role in the degenerative process of retinal cells. This study reports changes in retinal vascular network architecture in the P23H rat model of RP at different stages of retinal degeneration. Homozygous P23H line-3 rats of ages ranging from 18 days to 16 months were used in this study. Age-matched Sprague-Dawley (SD) rats were used as control animals. Vertical sections and wholemount retinas were immunolabeled for type IV collagen or stained using NADPH diaphorase histochemistry, and retinal vascular networks were drawn using a camera lucida. The superficial and deep capillary plexus (DCP) were fully developed at P18 in P23H rat retinas and showed no differences from the control animals. In 4-month-old P23H rat retinas, the superficial and intermediate capillary plexus were similar to those observed in age-matched SD rats, but a reduction in the DCP could be observed in these animals, with a significant decrease in both capillary density and capillary loops. At 16 months, the DCP was completely lost, and only vessels exhibiting an abnormal, tortuous dead-end could be observed. The middle capillary plexus had virtually disappeared at this age. Only perpendicular vessels connecting the superficial and DCP were found. The superficial plexus showed no changes in the vascular surface with age. In RP, photoreceptor loss is accompanied by degenerative changes in the retinal vascular network. The disruption of the capillary plexus, with loss of capillary density and capillary loops, can hamper the normal supply of oxygen and nutrients to retinal cells, thus accelerating retinal degeneration. Therefore, changes in retinal vascularization must be taken into account in the design of therapies targeting retinal degenerative diseases.

Effect of Chronic Hypoxia in Cognition on Childhood : Review Article

Background: Hypoxia is defined as the reduction of the normal oxygen supply. The hypoxia is traditionally classified as acute and chronic. Chronic hypoxia was classified into three subgroups: diffusion-limited hypoxia, hypoxemic hypoxia, and hypoxia due to a compromised perfusion of leaky micro vessels. Serious hypoxic-ischemic events are known to have an adverse impact on cognitive function. Aim: to review the evidence concerning the effect of chronic hypoxia on childhood cognitive outcomes including development and academic achievement. Materials and Methods: We used scientific websites such as PubMed, Google Scholar, and Research Gate to get related articles about this subject. Results: There were 15 articles included in this review including both research and review articles. Conclusion: It has been suggested that cognitive function including knowledge, attention, memory and Oxygen supply to the brain tissue may be decreased under hypoxia. Thus, brain desaturation and resultant biological process may be responsible for the impairment of cognitive function although the underlying mechanisms are still unclear

EFFECTS OF CHOKE RING DIMENSION ON THERMAL AND FLUID FLOW IN A SRU THERMAL REACTOR

The effects of choke ring dimension on the thermal and fluid flow in a practical SRU (sulfur recovery unit) thermal reactor are investigated numerically. It is found that zone 1 is a higher temperature region. In contrast, zone 2 is a lower temperature region. The average temperature for the rich oxygen supply is higher than that of normal oxygen supply. Without a choke ring, the temperature difference between zone 1 and zone 2 is smaller and the temperature in zone 1 becomes lower while the temperature in zone 2 becomes higher. In addition, the average temperature in zone 1 and the sulfur concentration at exit are the lowest without a choke ring. The reactor with a choke ring height of 0.74 m has the lowest peak temperature and the largest sulfur concentration at exit. Finally, with a choke ring height of 1.11 m, the blockage effect of the choke ring leads to the largest peak skin friction coefficient.

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876.

Despite the long‐known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1‐selective small‐molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high‐throughput screen against a library of ∼3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N‐(1H‐pyrazol‐4‐yl)quinoline‐4‐carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure–activity relationship explorations, single‐digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY‐876 [N 4‐[1‐(4‐cyanobenzyl)‐5‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl]‐7‐fluoroquinoline‐2,4‐dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo.

Oxygen diffusion: an enzyme-controlled variable parameter.

Previous oxygen microelectrode studies have shown that the oxygen diffusion coefficient (DO₂) increases during extracellular PO₂ decreases, while intracellular PO₂ remained unchanged and thus cell function (spike activity of neurons). Oxygen dependency of complex multicellular organisms requires a stable and adequate oxygen supply to the cells, while toxic concentrations have to be avoided. Oxygen brought to the tissue by convection diffuses through the intercellular and cell membranes, which are potential barriers to diffusion. In gerbil brain cortex, PO₂ and DO₂ were measured by membrane-covered and by bare gold microelectrodes, as were also spike potentials. Moderate respiratory hypoxia was followed by a primary sharp drop of tissue PO₂ that recovered to higher values concomitant with an increase of DO₂. A drop in intracellular PO₂ recovered immediately. Studies on the abdominal ganglion of aplysia californica showed similar results.Heterogeneity is a feature of both normal oxygen supply to tissue and supply due to a wide range of disturbances in oxygen supply. Oxygen diffusion through membranes is variable thereby ensuring adequate intracellular PO₂. Cell-derived glucosamine oxidase seems to regulate the polymerization/depolymerisation ratio of membrane mucopolysaccharides and thus oxygen diffusion.Variability of oxygen diffusion is a decisive parameter for regulating the supply/demand ratio of oxygen supply to the cell; this occurs in highly developed animals as well as in species of a less sophisticated nature. Autoregulation of oxygen diffusion is as important as the distribution/perfusion ratio of the capillary meshwork and as the oxygen extraction ratio in relation to oxygen consumption of the cell. Oxygen diffusion resistance is the cellular protection against luxury oxygen supply (which can result in toxic oxidative species leading to mutagenesis).

Heterogeneity in tissue oxygenation: from physiological variability in normal tissues to pathophysiological chaos in malignant tumours.

Heterogeneity is a feature of both normal oxygen supply to tissue and of a supply that is disturbed due to a wide range of different pathologies. Here, the physiological importance of heterogeneity of tissue oxygenation is revisited. The anatomical and functional basis for heterogeneity of blood flow, local and regional regulatory mechanisms in normal tissues and the pathophysiology of the failure of regulation will be examined.Under physiological conditions, regulation of blood flow distributions at global, regional and microregional levels play coordinated roles in ensuring adequate O2 supply to all tissue cells. How this is achieved may be organ-/organ layer-specific, depending on its function and priorities to match local O2 delivery to consumption. Examples where these regulatory mechanisms break down under conditions of ischaemia and shock will also be given.In contrast, pathologic heterogeneity in tissue oxygenation resulting from uncontrolled, chaotic growth as seen in malignant tumours represents a pathophysiological status that is not predictable which, in general, is associated with chronic and acute hypoxia. This can have fatal consequences due to hypoxia- induced (mal-)adaptive processes, malignant tumour progression and treatment resistance.

Comparative Metabolomics Analysis of Docosahexaenoic Acid Fermentation Processes by Schizochytrium sp. under Different Oxygen Availability Conditions

The intracellular metabolic profile characterization of Schizochytrium sp. throughout docosahexaenoic acid fermentation was investigated using gas chromatography-mass spectrometry (GC-MS). Metabolite profiles originating from Schizochytrium sp. under normal and limited oxygen supply conditions were distinctive and distinguished by principal components analysis (PCA). A total of more than 60 intracellular metabolites were detected and quantified with the levels of some metabolites involved in central carbon metabolism varying throughout both processes. Both fermentation processes were differentiated into three main phases by principal components analysis. Potential biomarkers responsible for distinguishing the different fermentation phases were identified as glutamic acid, proline, glycine, alanine, and glucose. In addition, alanine, glutamic acid, glucose, inositol, ornithine, and galactose were found to make great contribution for dry cell weight and fatty acid composition during normal and limited oxygen supply fermentations. Furthermore, significantly higher levels of succinate and several amino acids in cells of limited oxygen supply fermentation revealed that they might play important roles in resisting oxygen deficiency and increasing DHA synthesis during the lipid accumulation. These findings provide novel insights into the metabolomic characteristics during docosahexaenoic acid fermentation processes by Schizochytrium sp.

Abstract 3215: Metabolic alterations of cancer cell as potential anti-cancer target

Abstract In cancer cells, energy generating pathways are markedly altered like many other processes. Warburg described this effect as increase the rate of glycolysis in the expense of oxidative phosphorylation. Dysfunctional Mitochondria, not Oxygen insufficiency, cause cancer cells to produce inordinate amounts of Lactic acid. The fact that most cancers have poor vascular systems has led to assume that such cells are deprived of a normal supply of oxygen, and thus it was forced to switch for anaerobic glycolysis. Recently many experiments illustrated that, cancer cells keep using anaerobic glycolysis even under conditions where Oxygen is plentiful, resulting in high rates of lactate formation. This indicates; cancer cell switches to anaerobic glycolysis because it's in need for Lactic acid. In comparison to Morula's cell has higher concentration of Lactic acid, than other fully differentiated adult cells, at the same time it has less concentration than cancer cells. This means that Lactic acid is associated with poor differentiation and high proliferation of cells in both cancer and health situations. But after the cell has been specialized and became fully differentiated, Lactic acid starts losing this property. In this context, Lactic acid playing a pivotal role in cell transformation and p53 de-activation, at the same time it's interfere with signaling pathway to activate or enhance the activity of ERK 1/2, result in cell proliferation. Since there is direct link between p53 and COX by showing p53 induction correlated with an up regulation of COXI subunit expression at the mRNA level. So loss of p53 resulted in decreased COXII protein expression with concomitant decreases in COX enzyme activity, and thus halts Mitochondrial oxidative phosphorylation, at the same time force cells to become entirely dependent on glycolysis to meet energy demands. In response, cells start importing more Glucose into the Cytosol by increase the activity of GLUT, which it's under the control of Atypical PKC isozymes, these isozymes control insulin-stimulated glucose transport by promoting the translocation of glucose transporters to the plasma membrane. PKC isozymes are involved in a wide array of diverse cellular functions. Most isozymes (PKC-beta) are involved in proliferation, and differentiation, whereas (PKC-epsilon) is anti-apoptotic. PKC results in activation of Ras, this in turn results in activation of ERK 1/2, and PI3K. PI3K responsible for activation of MDM2, which results in inhibition p53 activity. And thus, over activation of PKC by Lactic acid results in halting p53, and enhancing the activity of Ras. So obviously Lactic acid has binding site in PKC's domain to activate it. But the difference in its activation in cancer and normal ES cells is that in ES cells is controlled by the amount of Lactic acid produced. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3215. doi:1538-7445.AM2012-3215

Effects of hypoxia on color vision with emphasis on the mesopic range

The ability to see clear images, to resolve fine spatial detail in faint objects, to see and appreciate small color differences, to discriminate motion direction and to detect rapidly flickering lights over a very large range of natural illumination is something we often take for granted. Good vision is our expectation, but as we grow older, we become aware of very gradual visual deficits that in some cases can lead to severe loss of vision. These deficits are often caused by changes in the optics of the eye and/or the retina. A normal supply of oxygen and nutrients to the retina is essential to maintain good vision, but when the supporting mechanisms fail, local hypoxia can trigger structural changes that affect normal vision. In this article, we review endogenous and exogenous factors that cause changes in the supply of oxygen to the eye and how these can affect color vision when oxygen demands vary with light adaptation level. We review the latest color vision assessment techniques and show how the level of retinal oxygenation can affect color vision in normal trichromats and in subjects with congenital color deficiencies. We also discuss acquired loss of color vision in relation to hypoxia and how it may soon become possible to use advanced vision and optometric tests to detect the earliest signs of disease that precede clinical diagnosis and to monitor disease progression and effectiveness of treatment. We explore how knowledge of normal differences between photopic and mesopic visual performance and the expected limits of normal variability as a function of age can help achieve this goal.

Oxygen Sensing, Cardiac Ischemia, HIF-1&amp;#945; and Some Emerging Concepts

Oxygen plays a critical role in the perpetuation and propagation of almost all forms of life. The primary site of cellular oxygen consumption is the mitochondrial electron transport chain and in addition, oxygen is also used as a substrate for various enzymes involved in cellular homeostasis. Although our knowledge of the biochemistry and physiology of oxygen transport is century old, recent development of sophisticated tools of biophysical chemistry revealed that tissue oxygenation and oxygen sensing is a highly evolved process, especially in mammals. Perturbation of normal oxygen supply is associated with diseases like tumorigenesis, myocardial infarction and stroke. Available information suggests that when tissue oxygen supply is limited, mitochondria emanate signals involving reactive oxygen species generation which in turn stabilizes oxygen sensing transcription factor HIF-1. Upon stabilization, HIF-1 elicits necessary genetic response to cope with the diminished oxygen level. In view of such critical role of HIF-1 in cellular oxygen sensing, recently there has been a heightened interest in understanding the biology of HIF-1 in the context of cardiovascular system. The following review describes some of the recent advances in this regard.