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Oxidative Medicine and Cellular... 2020Cancer is a major disease burden worldwide. In recent years, in addition to surgical resection, radiotherapy and chemotherapy are recognized as the most effective... (Review)
Review
Cancer is a major disease burden worldwide. In recent years, in addition to surgical resection, radiotherapy and chemotherapy are recognized as the most effective methods for treating solid tumors. These methods have been introduced to treat tumors of different origins and stages clinically. However, due to insufficient blood flow and oxygen (O) supply in solid tumors, hypoxia is caused, leading to decreased sensitivity of tumor cells and poor therapeutic effects. In addition, hypoxia will also lead to resistance to most anticancer drugs, accelerate malignant progress, and increase metastasis. In solid tumors, adequate O supply and adequate delivery of anticancer drugs are essential to improve radiotherapy and chemotherapy sensitivity. In recent decades, the researches on relieving tumor hypoxia have attracted researchers' extensive attention and achieved good results. However, as far as we know, there is no detailed review of the researches on alleviating tumor hypoxia. Therefore, in this contribution, we hope to give an overview of the researches on methods to improve tumor hypoxia environment and summarize their effect and application in tumor therapy, to provide a methodological reference for the research and development of new antitumor agents.
Topics: Animals; Biomedical Research; Blood Circulation; Cell Hypoxia; Humans; Neoplasms; Oxygen; Tumor Microenvironment
PubMed: 33343807
DOI: 10.1155/2020/5721258 -
Scientific Reports Mar 2021Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply...
Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the "Warburg Effect". We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.
Topics: Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Models, Biological; Oxygen; Protein Stability; Stochastic Processes; Tumor Microenvironment
PubMed: 33707510
DOI: 10.1038/s41598-021-85184-8 -
Frontiers in Bioscience (Landmark... Jul 2022This report aims to detail the use of the phosphorescence oxygen analyzer for investigation of thymic responses to pharmaceutical agents, in particular...
BACKGROUND
This report aims to detail the use of the phosphorescence oxygen analyzer for investigation of thymic responses to pharmaceutical agents, in particular immunosuppressants and immunomodulators. Sirolimus (a highly specific inhibitor of the 'molecular target of rapamycin', mTOR) and ozanimod (an agonist of the sphingosine 1-phosphate receptor, recently approved for treatment of multiple sclerosis and ulcerative colitis) are used for this purpose.
METHODS
Thymic fragments from mice were placed in glass vials containing phosphate-buffered saline, bovine albumin, and Pd(II) meso-tetra (sulfophenyl) tetrabenzoporphyrin. The vials were sealed from air, and the cellular oxygen consumption was monitored as function of time.
RESULTS
The decline of dissolved oxygen concentration with time (d[O2]/d) was linear; thus, its rate (thymocyte respiration) was expressed as μM O2 min-1. Cyanide inhibited respiration, confirming the oxygen consumption was in cytochrome oxidase. In age-matched mice, the rate of thymocyte respiration (mean ± SD, in μM O2 min-1 mg-1) was 0.046 ± 0.011 (median = 0.043, range = 0.028 to 0.062, n = 10). In thymic fragments from littermates, this rate was inhibited in the presence of sirolimus (16% lower) or ozanimod (29% lower).
CONCLUSIONS
Thymocyte respiration can serve as a surrogate biomarker for studying the mode-of-action and the cytotoxicity of immunotoxins and immunosuppressants.
Topics: Animals; Cattle; Cell Respiration; Immunosuppressive Agents; Mice; Oxygen; Oxygen Consumption; Sirolimus
PubMed: 36042174
DOI: 10.31083/j.fbl2708230 -
Cellular and Molecular Life Sciences :... Mar 2021Various factors of the tissue microenvironment such as the oxygen concentration influence the host-pathogen interaction. During the past decade, hypoxia-driven signaling... (Review)
Review
Various factors of the tissue microenvironment such as the oxygen concentration influence the host-pathogen interaction. During the past decade, hypoxia-driven signaling via hypoxia-inducible factors (HIF) has emerged as an important factor that affects both the pathogen and the host. In this chapter, we will review the current knowledge of this complex interplay, with a particular emphasis given to the impact of hypoxia and HIF on the inflammatory and antimicrobial activity of myeloid cells, the bacterial responses to hypoxia and the containment of bacterial infections under oxygen-limited conditions. We will also summarize how low oxygen concentrations influence the metabolism of neutrophils, macrophages and dendritic cells. Finally, we will discuss the consequences of hypoxia and HIFα activation for the invading pathogen, with a focus on Pseudomonas aeruginosa, Mycobacterium tuberculosis, Coxiella burnetii, Salmonella enterica and Staphylococcus aureus. This includes a description of the mechanisms and microbial factors, which the pathogens use to sense and react to hypoxic conditions.
Topics: Animals; Cell Hypoxia; Host-Pathogen Interactions; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mycobacterium tuberculosis; Myeloid Cells; Oxygen; Pseudomonas aeruginosa; Staphylococcus aureus
PubMed: 33125509
DOI: 10.1007/s00018-020-03684-8 -
Journal of Molecular Medicine (Berlin,... Jan 2021Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are... (Review)
Review
Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.
Topics: Animals; Cell Respiration; Electron Transport Chain Complex Proteins; Humans; Mitochondria
PubMed: 33201259
DOI: 10.1007/s00109-020-02004-8 -
International Journal of Molecular... Aug 2021The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO), characterised by a high rate of metabolites circulating through... (Review)
Review
The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome-gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.
Topics: Animals; Cell Hypoxia; Gastrointestinal Microbiome; Homeostasis; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Oxygen
PubMed: 34502078
DOI: 10.3390/ijms22179170 -
The EMBO Journal Jun 2024The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often...
The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.
Topics: Oxygen; Adipocytes; Humans; Cell Differentiation; Cell Culture Techniques; Animals; Glycolysis; Hepatocytes; Cell Hypoxia; Mitochondria; Mice; Hypoxia-Inducible Factor 1, alpha Subunit; Cells, Cultured; Glucose; Macrophages
PubMed: 38580776
DOI: 10.1038/s44318-024-00084-7 -
Critical Care (London, England) Jul 2022During refractory cardiogenic shock and cardiac arrest, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used to restore a circulatory output. However, it... (Review)
Review
During refractory cardiogenic shock and cardiac arrest, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used to restore a circulatory output. However, it also impacts significantly arterial oxygenation. Recent guidelines of the Extracorporeal Life Support Organization (ELSO) recommend targeting postoxygenator partial pressure of oxygen (PO) around 150 mmHg. In this narrative review, we intend to summarize the rationale and evidence for this PO target recommendation. Because this is the most used configuration, we focus on peripheral VA-ECMO. To date, clinicians do not know how to set the sweep gas oxygen fraction (FO). Because of the oxygenator's performance, arterial hyperoxemia is common during VA-ECMO support. Interpretation of oxygenation is complex in this setting because of the dual circulation phenomenon, depending on both the native cardiac output and the VA-ECMO blood flow. Such dual circulation results in dual oxygenation, with heterogeneous oxygen partial pressure (PO) along the aorta, and heterogeneous oxygenation between organs, depending on the mixing zone location. Data regarding oxygenation during VA-ECMO are scarce, but several observational studies have reported an association between hyperoxemia and mortality, especially after refractory cardiac arrest. While hyperoxemia should be avoided, there are also more and more studies in non-ECMO patients suggesting the harm of a too restrictive oxygenation strategy. Finally, setting FO to target strict normoxemia is challenging because continuous monitoring of postoxygenator oxygen saturation is not widely available. The threshold of PO around 150 mmHg is supported by limited evidence but aims at respecting a safe margin, avoiding both hypoxemia and severe hyperoxemia.
Topics: Extracorporeal Membrane Oxygenation; Heart Arrest; Humans; Oxygen; Shock, Cardiogenic
PubMed: 35883117
DOI: 10.1186/s13054-022-04102-0 -
Trends in Microbiology Feb 2023Depending on their physiology and metabolism, bacteria can carry out diverse redox processes for energy acquisition, which facilitates adaptation to environmental or... (Review)
Review
Depending on their physiology and metabolism, bacteria can carry out diverse redox processes for energy acquisition, which facilitates adaptation to environmental or host-associated niches. Of these processes, respiration, using oxygen or alternative terminal electron acceptors, is energetically the most favorable in heterotrophic bacteria. The biofilm lifestyle, a coordinated multicellular behavior, is ubiquitous in bacteria and is regulated by a variety of intrinsic and extrinsic cues. Respiration of distinct electron acceptors has been shown to induce biofilm formation or dispersal. The notion of biofilm formation regulation by electron acceptor availability and respiration has often been considered species-specific. However, recent evidence suggests that this phenomenon can be strain-specific, even in strains sharing the same functional respiratory pathways, thereby implying subtle regulatory mechanisms. On this basis, I argue that induction of biofilm formation by sensing and respiration of electron acceptors might direct subgroups of redox-specialized strains to occupy certain niches. A palette of respiration and electron-transfer-mediated microbial social interactions within biofilms may broaden ecological opportunities. The strain specificity of this phenomenon represents an important opportunity to identify key molecular mechanisms and their ecophysiological significance, which in turn may lay the ground for applications in areas ranging from biotechnology to the prevention of antimicrobial resistance.
Topics: Biofilms; Oxidation-Reduction; Bacteria; Oxygen; Respiration
PubMed: 36075785
DOI: 10.1016/j.tim.2022.08.007 -
Molecules (Basel, Switzerland) Dec 2020Oxidative stress-induced lipid peroxidation (LPO) due to neutrophil-derived reactive oxygen species plays a key role in the early stage of the acute respiratory distress...
BACKGROUND
Oxidative stress-induced lipid peroxidation (LPO) due to neutrophil-derived reactive oxygen species plays a key role in the early stage of the acute respiratory distress syndrome (ARDS). Monitoring of oxidative stress in this patient population is of great interest, and, ideally, this can be done noninvasively. Recently, propionaldehyde, a volatile chemical compound (VOC) released during LPO, was identified in the breath of lung transplant recipients as a marker of oxidative stress. The aim of the present study was to identify if markers of oxidative stress appear in the oxygenator outflow gas of patients with severe ARDS treated with veno-venous extracorporeal membrane oxygenation (ECMO).
METHODS
The present study included patients with severe ARDS treated with veno-venous ECMO. Concentrations of acetone, isoprene, and propionaldehyde were measured in inspiratory air, exhaled breath, and oxygenator inflow and outflow gas at corresponding time points. Ion-molecule reaction mass spectrometry was used to measure VOCs in a sequential order within the first 24 h and on day three after ECMO initiation.
RESULTS
Nine patients (5 female, 4 male; age = 42.1 ± 12.2 year) with ARDS and already established ECMO therapy (pre-ECMO PaO/FiO = 44.0 ± 11.5 mmHg) were included into analysis. VOCs appeared in comparable amounts in breath and oxygenator outflow gas (acetone: 838 (422-7632) vs. 1114 (501-4916) ppbv; isoprene: 53.7 (19.5-244) vs. 48.7 (37.9-108) ppbv; propionaldehyde: 53.7 (32.1-82.2) vs. 42.9 (24.8-122) ppbv). Concentrations of acetone, isoprene, and propionaldehyde in breath and oxygenator outflow gas showed a parallel course with time.
CONCLUSIONS
Acetone, isoprene, and propionaldehyde appear in breath and oxygenator outflow gas in comparable amounts. This allows for the measurement of these VOCs in a critically ill patient population via the ECMO oxygenator outflow gas without the need of ventilator circuit manipulation.
Topics: Adolescent; Adult; Aldehydes; Breath Tests; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Middle Aged; Oxygenators; Pilot Projects; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 33396196
DOI: 10.3390/molecules26010145