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Redox Biology Oct 2019Hyperbaric oxygen (HBO) is breathed during hyperbaric oxygen therapy and during certain undersea pursuits in diving and submarine operations. What limits exposure to HBO... (Review)
Review
Hyperbaric oxygen (HBO) is breathed during hyperbaric oxygen therapy and during certain undersea pursuits in diving and submarine operations. What limits exposure to HBO in these situations is the acute onset of central nervous system oxygen toxicity (CNS-OT) following a latent period of safe oxygen breathing. CNS-OT presents as various non-convulsive signs and symptoms, many of which appear to be of brainstem origin involving cranial nerve nuclei and autonomic and cardiorespiratory centers, which ultimately spread to higher cortical centers and terminate as generalized tonic-clonic seizures. The initial safe latent period makes the use of HBO practical in hyperbaric and undersea medicine; however, the latent period is highly variable between individuals and within the same individual on different days, making it difficult to predict onset of toxic indications. Consequently, currently accepted guidelines for safe HBO exposure are highly conservative. This review examines the disorder of CNS-OT and summarizes current ideas on its underlying pathophysiology, including specific areas of the CNS and fundamental neural and redox signaling mechanisms that are thought to be involved in seizure genesis and propagation. In addition, conditions that accelerate the onset of seizures are discussed, as are current mitigation strategies under investigation for neuroprotection against redox stress while breathing HBO that extend the latent period, thus enabling safer and longer exposures for diving and medical therapies.
Topics: Animals; Central Nervous System; Humans; Hyperbaric Oxygenation; Oxidation-Reduction; Oxygen; Respiration
PubMed: 30902504
DOI: 10.1016/j.redox.2019.101159 -
American Journal of Physiology. Cell... Jan 2023Metastasis is the leading cause of mortality in most patients with cancer. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain... (Review)
Review
Metastasis is the leading cause of mortality in most patients with cancer. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain poorly understood. Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature. In this review, we describe the roles of hypoxia and hypoxia-inducible factor (HIF) signaling in the metastatic cascade, with an emphasis on recent biological insights from in vivo studies.
Topics: Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasm Metastasis; Neoplasms; Oxygen; Signal Transduction; Tumor Microenvironment; Tumor Hypoxia
PubMed: 36409179
DOI: 10.1152/ajpcell.00158.2022 -
Journal of Cardiothoracic Surgery Mar 2023The management of the oxygenator can be prolonged in the long-term procedures especially during extracorporeal membrane oxygenation (ECMO) for bridge to transplant or...
BACKGROUND
The management of the oxygenator can be prolonged in the long-term procedures especially during extracorporeal membrane oxygenation (ECMO) for bridge to transplant or bridge to recovery. Long-term use often involves an overrun of the time of use with respect to certification of the oxygenating module of 14 days, for the maintenance of performance and efficiency of the oxygenator. The evaluation of the long-term oxygenator efficiency is complex and depends on the: patient pathology, ECMO configuration, the management of coagulation and anticoagulation, materials selection and circuit components, the structure, design and performance of the oxygenator. In this context we investgated the long-term performance of the A.L.ONE Eurosets ECMO oxygenator in relation to the parameters prodromal to replacement.
METHODS
We retrospectively collected eight years data from Anthea Hospital GVM Care & Research, Bari, Italy on the long-term use exceeding 14 days of Eurosets A.L.ONE ECMO Adult oxygenator in Polymetylpentene fiber, for ECMO procedures, including the procedures: Veno Arterial (VA) ECMO post-cardiotomy or not, veno-venous (VV) ECMO. The primary end points were the evaluation of Gas Transfer: oxygen partial pressure (PO) post oxygenator, Carbon dioxide partial pressure (PCO) post oxygenator, the oxygen transfer across the oxygenator membrane V'O, differential CO content across oxygenator; Pressure monitoring: oxygenator pressure Drop in relation to Blood flow rate (BFR) (ΔP); Hematologic values: Hemoglobin, Fibrinogen, Platelets, aPTT, D-Dimer, LDH.
RESULTS
Nine VA ECMO patients who used the oxygenator for 18.5 days and two VV ECMO patients who used the oxygenators for 17.2 days on the seventeenth days reported average values PaO (267 ± 29 mmHg); PaCO (34 ± 4 mmHg) with gas blender values set to 3.8 ± 0.6 L/min of air and a FiO of 78 ± 5%; the transfer across the oxygenator membrane V'O was 189 ± 43 (ml/min/m). The mean peak of partial pressure of carbon dioxide from the gas exhaust of oxygenator (PCO) was 38 ± 4 mmHg; differential CO across the oxygenator "pre-oxygenator PCO-post-oxygenator PCO" (18 ± 6 mmHg); the mean blood flow rate (BFR) 4.5 ± 0.6 (L/minute); the pump revolution per minutes mean maximum rate was 4254 ± 345 (RPM); the mean pressure drop (ΔP) was 76 ± 12 mmHg; the mean peak of d-dimers (DDs) was 23.6 ± 0.8 mg / dL; the mean peak of LDH was 230 ± 55 (mg/dl); fibrinogen mean peak 223 ± 40 (mg/dl).
CONCLUSIONS
The performance of the Eurosets A.L.ONE ECMO Adult polymethylpentene fiber oxygenator in our experience has proven efficiency in terms of O uptake and CO removal, blood fluid dynamics, metabolic compensation and heat exchange in the long-term treatment. The device was safe without iatrogenic problems over a period of 14 days in the patients undergoing ECMO VA and in all patients undergoing VV ECMO with continuous administration of anticoagulation therapy.
Topics: Humans; Adult; Extracorporeal Membrane Oxygenation; Carbon Dioxide; Retrospective Studies; Oxygenators, Membrane; Oxygen
PubMed: 36998079
DOI: 10.1186/s13019-023-02190-9 -
Biochemical Pharmacology Dec 2020Acute myeloid leukemia (AML) is a heterogeneous disease with variable presentation, molecular phenotype, and cytogenetic abnormalities and has seen very little... (Review)
Review
Acute myeloid leukemia (AML) is a heterogeneous disease with variable presentation, molecular phenotype, and cytogenetic abnormalities and has seen very little improvement in patient survival over the last few decades. This heterogeneity supports poor prognosis partially through the variability in response to the standard chemotherapy. Further understanding of molecular heterogeneity has promoted the development of novel treatments, some of which target mitochondrial metabolism and function. This review discusses the relative dependency that AML cells have on mitochondrial function, and the ability to pivot this reliance to target important subsets of AML cells, including leukemia stem cells (LSCs). LSCs are tumor-initiating cells that are resistant to standard chemotherapy and promote the persistence and relapse of AML. Historically, LSCs have been targeted based on immunophenotype, but recent developments in the understanding of LSC metabolism has demonstrated unique abilities to target LSCs while sparing normal hematopoietic stem cells (HSCs) through inhibition of mitochondrial function. Here we highlight the use of small molecules that have been demonstrated to effectively target mitochondrial function. IACS-010759 and ME-344 target the electron transport chain (ETC) to inhibit oxidative phosphorylation (OXPHOS). The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.
Topics: Animals; Antineoplastic Agents; Cell Respiration; Drug Delivery Systems; Humans; Leukemia, Myeloid, Acute; Mitochondria; Neoplastic Stem Cells
PubMed: 33011159
DOI: 10.1016/j.bcp.2020.114253 -
American Journal of Respiratory Cell... Oct 2023
Topics: Oxygen; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Organogenesis; Lung
PubMed: 37478332
DOI: 10.1165/rcmb.2023-0247ED -
Free Radical Biology & Medicine Aug 2019The ability to harvest light to drive chemical reactions and gain energy provided microbes access to high energy electron donors which fueled primary productivity,... (Review)
Review
The ability to harvest light to drive chemical reactions and gain energy provided microbes access to high energy electron donors which fueled primary productivity, biogeochemical cycles, and microbial evolution. Oxygenic photosynthesis is often cited as the most important microbial innovation-the emergence of oxygen-evolving photosynthesis, aided by geologic events, is credited with tipping the scale from a reducing early Earth to an oxygenated world that eventually lead to complex life. Anoxygenic photosynthesis predates oxygen-evolving photosynthesis and played a key role in developing and fine-tuning the photosystem architecture of modern oxygenic phototrophs. The release of oxygen as a by-product of metabolic activity would have caused oxidative damage to anaerobic microbiota that evolved under the anoxic, reducing conditions of early Earth. Photosynthetic machinery is particularly susceptible to the adverse effects of oxygen and reactive oxygen species and these effects are compounded by light. As a result, phototrophs employ additional detoxification mechanisms to mitigate oxidative stress and have evolved alternative oxygen-dependent enzymes for chlorophyll biosynthesis. Phylogenetic reconstruction studies and biochemical characterization suggest photosynthetic reactions centers, particularly in Cyanobacteria, evolved to both increase efficiency of electron transfer and avoid photodamage caused by chlorophyll radicals that is acute in the presence of oxygen. Here we review the oxygen and reactive oxygen species detoxification mechanisms observed in extant anoxygenic and oxygenic photosynthetic bacteria as well as the emergence of these mechanisms over evolutionary time. We examine the distribution of phototrophs in modern systems and phylogenetic reconstructions to evaluate the emergence of mechanisms to mediate oxidative damage and highlight changes in photosystems and reaction centers, chlorophyll biosynthesis, and niche space in response to oxygen production. This synthesis supports an emergence of HS-driven anoxygenic photosynthesis in Cyanobacteria prior to the evolution of oxygenic photosynthesis and underscores a role for the former metabolism in fueling fine-tuning of the oxygen evolving complex and mechanisms to repair oxidative damage. In contrast, we note the lack of elaborate mechanisms to deal with oxygen in non-cyanobacterial anoxygenic phototrophs suggesting these microbes have occupied similar niche space throughout Earth's history.
Topics: Biological Evolution; Cyanobacteria; Oxidation-Reduction; Oxygen; Photosynthesis; Phototrophic Processes
PubMed: 31078729
DOI: 10.1016/j.freeradbiomed.2019.05.003 -
British Journal of Cancer Feb 2023Pivotal research led by Louis Harold Gray in the 1950s suggested that oxygen plays a vital role during radiotherapy. By proving that tumours have large necrotic cores... (Review)
Review
Pivotal research led by Louis Harold Gray in the 1950s suggested that oxygen plays a vital role during radiotherapy. By proving that tumours have large necrotic cores due to hypoxia and that hypoxic cells require significantly larger doses of ionising radiation to achieve the same cell kill, Thomlinson and Gray inspired the subsequent decades of research into better defining the mechanistic role of molecular oxygen at the time of radiation. Ultimately, the work pioneered by Thomlinson and Gray led to numerous elegant studies which demonstrated that tumour hypoxia predicts for poor patient outcomes. Furthermore, this subsequently resulted in investigations into markers and measurement of hypoxia, as well as modification strategies. However, despite an abundance of pre-clinical data supporting hypoxia-targeted treatments, there is limited widespread application of hypoxia-targeted therapies routinely used in clinical practice. Significant contributing factors underpinning disappointing clinical trial results include the use of model systems which are more hypoxic than human tumours and a failure to stratify patients based on levels of hypoxia. However, translating the original findings of Thomlinson and Gray remains a research priority with the potential to significantly improve patient outcomes and specifically those receiving radiotherapy.
Topics: Humans; Cell Hypoxia; Neoplasms; Hypoxia; Radiobiology; Oxygen; Lung Neoplasms
PubMed: 36344595
DOI: 10.1038/s41416-022-02041-9 -
The International Journal of Artificial... May 2023Aim of this work was to characterize possible central anatomical configurations in which a future artificial lung (AL) could be connected, in terms of oxygenation...
OBJECTIVES
Aim of this work was to characterize possible central anatomical configurations in which a future artificial lung (AL) could be connected, in terms of oxygenation performance.
METHODS
Pulmonary and systemic circulations were simulated using a numerical and an in vitro approach. The in vitro simulation was carried out in a mock loop in three phases: (1) normal lung, (2) pulmonary shunt (50% and 100%), and (3) oxygenator support in three anatomical configurations: right atrium-pulmonary artery (RA-PA), pulmonary artery-left atrium (PA-LA), and aorta-left atrium (Ao-LA). The numerical simulation was performed for the oxygenator support phase. The oxygen saturation (SO) of the arterial blood was plotted over time for two percentages of pulmonary shunt and three blood flow rates through the oxygenator.
RESULTS
During the pulmonary shunt phase, SO reached a steady state value (of 68% for a 50% shunt and of nearly 0% for a 100% shunt) 20 min after the shunt was set. During the oxygenator support phase, physiological values of SO were reached for RA-PA and PA-LA, in case of a 50% pulmonary shunt. For the same conditions, Ao-LA could reach a maximum SO of nearly 60%. Numerical results were congruous to the in vitro simulation ones.
CONCLUSIONS
Both in vitro and numerical simulations were able to properly characterize oxygenation properties of a future AL depending on its placement. Different anatomical configurations perform differently in terms of oxygenation. Right to right and right to left connections perform better than left to left ones.
Topics: Lung; Pulmonary Artery; Heart Atria; Oxygenators; Ventilators, Mechanical; Oxygen
PubMed: 37051677
DOI: 10.1177/03913988231168163 -
Cells Dec 2023Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia...
Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia to regulate several target gene expressions. Nevertheless, in the skeletal muscle satellite stem cells (SCs), an oxygen level-independent regulation of HIF-1α has been observed. Although HIF-1α has been highlighted as a SC function regulator, its spatio-temporal expression and role during myogenic progression remain controversial. Herein, using biomolecular, biochemical, morphological and electrophysiological analyses, we analyzed HIF-1α expression, localization and role in differentiating murine C2C12 myoblasts and SCs under normoxia. In addition, we evaluated the role of matrix metalloproteinase (MMP)-9 as an HIF-1α effector, considering that MMP-9 is involved in myogenesis and is an HIF-1α target in different cell types. HIF-1α expression increased after 24/48 h of differentiating culture and tended to decline after 72 h/5 days. Committed and proliferating mononuclear myoblasts exhibited nuclear HIF-1α expression. Differently, the more differentiated elongated and parallel-aligned cells, which are likely ready to fuse with each other, show a mainly cytoplasmic localization of the factor. Multinucleated myotubes displayed both nuclear and cytoplasmic HIF-1α expression. The MMP-9 and MyoD (myogenic activation marker) expression synchronized with that of HIF-1α, increasing after 24 h of differentiation. By means of silencing HIF-1α and MMP-9 by short-interfering RNA and MMP-9 pharmacological inhibition, this study unraveled MMP-9's role as an HIF-1α downstream effector and the fact that the HIF-1α/MMP-9 axis is essential in morpho-functional cell myogenic commitment.
Topics: Animals; Mice; Cell Differentiation; Matrix Metalloproteinase 9; Myoblasts, Skeletal; Oxygen; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia
PubMed: 38132171
DOI: 10.3390/cells12242851 -
Cells Dec 2021Mitochondrial dehydrogenases are differentially stimulated by Ca. Ca has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the...
Mitochondrial dehydrogenases are differentially stimulated by Ca. Ca has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca effects are biphasic: small increases in Ca concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca-dependent O utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific.
Topics: Animals; Calcium; Cell Respiration; Energy Metabolism; Kidney; Mitochondria, Heart; Models, Biological; Oxidative Phosphorylation; Oxygen Consumption; Rats, Sprague-Dawley; Substrate Specificity; Time Factors; Rats
PubMed: 35011693
DOI: 10.3390/cells11010131