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Therapeutic targeting of the hypoxic tumour microenvironment.
Singleton, DC, Macann, A, Wilson, WR
Nature reviews. Clinical oncology. 2021;(12):751-772
Abstract
Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.
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Oxygen and reactive oxygen species-dependent regulation of plant growth and development.
Considine, MJ, Foyer, CH
Plant physiology. 2021;(1):79-92
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Oxygen and reactive oxygen species (ROS) have been co-opted during evolution into the regulation of plant growth, development, and differentiation. ROS and oxidative signals arising from metabolism or phytohormone-mediated processes control almost every aspect of plant development from seed and bud dormancy, liberation of meristematic cells from the quiescent state, root and shoot growth, and architecture, to flowering and seed production. Moreover, the phytochrome and phytohormone-dependent transmissions of ROS waves are central to the systemic whole plant signaling pathways that integrate root and shoot growth. The sensing of oxygen availability through the PROTEOLYSIS 6 (PRT6) N-degron pathway functions alongside ROS production and signaling but how these pathways interact in developing organs remains poorly understood. Considerable progress has been made in our understanding of the nature of hydrogen peroxide sensors and the role of thiol-dependent signaling networks in the transmission of ROS signals. Reduction/oxidation (redox) changes in the glutathione (GSH) pool, glutaredoxins (GRXs), and thioredoxins (TRXs) are important in the control of growth mediated by phytohormone pathways. Although, it is clear that the redox states of proteins involved in plant growth and development are controlled by the NAD(P)H thioredoxin reductase (NTR)/TRX and reduced GSH/GRX systems of the cytosol, chloroplasts, mitochondria, and nucleus, we have only scratched the surface of this multilayered control and how redox-regulated processes interact with other cell signaling systems.
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How Microbes Evolved to Tolerate Oxygen.
Khademian, M, Imlay, JA
Trends in microbiology. 2021;(5):428-440
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Ancient microbes invented biochemical mechanisms and assembled core metabolic pathways on an anoxic Earth. Molecular oxygen appeared far later, forcing microbes to devise layers of defensive tactics that fend off the destructive actions of both reactive oxygen species (ROS) and oxygen itself. Recent work has pinpointed the enzymes that ROS attack, plus an array of clever protective strategies that abet the well known scavenging systems. Oxygen also directly damages the low-potential metal centers and radical-based mechanisms that optimize anaerobic metabolism; therefore, committed anaerobes have evolved customized tactics that defend these various enzymes from occasional oxygen exposure. Thus a more comprehensive, detailed, and surprising view of oxygen toxicity is coming into view.
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HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxic regulation of preimplantation embryos: lessons from human embryonic stem cells.
Houghton, FD
Reproduction (Cambridge, England). 2021;(1):F41-F51
Abstract
Development of the preimplantation embryo is reliant on nutrients present in the milieu of the reproductive tract. While carbohydrates, amino acids, lipids, and micronutrients are often considered when discussing preimplantation embryo nutrition, environmental oxygen is frequently overlooked. Although oxygen is not classically considered a nutrient, it is an important component of the in vitro culture environment and a critical regulator of cellular physiology. Oxygen is required to sustain an oxidative metabolism but when oxygen becomes limited, cells mount a physiological response driven by a family of transcription factors termed 'hypoxia inducible factors' which promote expression of a multitude of oxygen sensitive genes. It is this hypoxic response that is responsible not only for the switch to a glycolytic metabolism but also for a plethora of other cellular responses. There has been much debate in recent years over which environmental oxygen tension is preferential for the culture of preimplantation embryos. The review will evaluate this question and highlights how research using human embryonic stem cells can inform our understanding of why culturing under physiological oxygen tensions may be beneficial for the development of embryos generated through clinical in vitro fertilisation.
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Cysteine, glutathione and a new genetic code: biochemical adaptations of the primordial cells that spread into open water and survived biospheric oxygenation.
Moosmann, B, Schindeldecker, M, Hajieva, P
Biological chemistry. 2020;(2):213-231
Abstract
Life most likely developed under hyperthermic and anaerobic conditions in close vicinity to a stable geochemical source of energy. Epitomizing this conception, the first cells may have arisen in submarine hydrothermal vents in the middle of a gradient established by the hot and alkaline hydrothermal fluid and the cooler and more acidic water of the ocean. To enable their escape from this energy-providing gradient layer, the early cells must have overcome a whole series of obstacles. Beyond the loss of their energy source, the early cells had to adapt to a loss of external iron-sulfur catalysis as well as to a formidable temperature drop. The developed solutions to these two problems seem to have followed the principle of maximum parsimony: Cysteine was introduced into the genetic code to anchor iron-sulfur clusters, and fatty acid unsaturation was installed to maintain lipid bilayer viscosity. Unfortunately, both solutions turned out to be detrimental when the biosphere became more oxidizing after the evolution of oxygenic photosynthesis. To render cysteine thiol groups and fatty acid unsaturation compatible with life under oxygen, numerous counter-adaptations were required including the advent of glutathione and the addition of the four latest amino acids (methionine, tyrosine, tryptophan, selenocysteine) to the genetic code. In view of the continued diversification of derived antioxidant mechanisms, it appears that modern life still struggles with the initially developed strategies to escape from its hydrothermal birthplace. Only archaea may have found a more durable solution by entirely exchanging their lipid bilayer components and rigorously restricting cysteine usage.
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A narrative review of hydrogen-oxygen mixture for medical purpose and the inhaler thereof.
Lin, HY, Lai, PC, Chen, WL
Medical gas research. 2020;(4):193-200
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Recent development regarding mixture of H2 (concentration of ~66%) with O2 (concentration of ~34%) for medical purpose, such as treatment of coronavirus disease-19 (COVID-19) patients, is introduced. Furthermore, the design principles of a hydrogen inhaler which generates mixture of hydrogen (~66%) with oxygen (~34%) for medical purpose are proposed. With the installation of the liquid blocking module and flame arresters, the air pathway of the hydrogen inhaler is divided by multiple isolation zones to prevent any unexpected explosion propagating from one zone to the other. An integrated filtering/cycling module is utilized to purify the impurity, and cool down the temperature of the electrolytic module to reduce the risk of the explosion. Moreover, a nebulizer is provided to selectively atomize the water into vapor which is then mixed with the filtered hydrogen-oxygen mix gas, such that the static electricity of a substance hardly occurs to reduce the risk of the explosion. Furthermore, hydrogen concentration detector is installed to reduce the risk of hydrogen leakage. Result shows that the hydrogen inhaler implementing the aforesaid design rules could effectively inhibit the explosion, even ignition at the outset of the hydrogen inhaler which outputs hydrogen-oxygen gas (approximately 66% hydrogen: 34% oxygen).
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Cellular adaptation to hypoxia through hypoxia inducible factors and beyond.
Lee, P, Chandel, NS, Simon, MC
Nature reviews. Molecular cell biology. 2020;(5):268-283
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Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.
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Wasteful, essential, evolutionary stepping stone? The multiple personalities of the photorespiratory pathway.
Fernie, AR, Bauwe, H
The Plant journal : for cell and molecular biology. 2020;(4):666-677
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The photorespiratory pathway, in short photorespiration, is a metabolic repair system that enables the CO2 fixation enzyme Rubisco to sustainably operate in the presence of oxygen, that is, during oxygenic photosynthesis of plants and cyanobacteria. Photorespiration is necessary because an auto-inhibitory metabolite, 2-phosphoglycolate (2PG), is produced when Rubisco binds oxygen instead of CO2 as a substrate and must be removed, to avoid collapse of metabolism, and recycled as efficiently as possible. The basic principle of recycling 2PG very likely evolved several billion years ago in connection with the evolution of oxyphotobacteria. It comprises the multi-step combination of two molecules of 2PG to form 3-phosphoglycerate. The biochemistry of this process dictates that one out of four 2PG carbons is lost as CO2 , which is a long-standing plant breeders' concern because it represents by far the largest fraction of respiratory processes that reduce gross-photosynthesis of major crops down to about 50% and less, lowering potential yields. In addition to the ATP needed for recycling of the 2PG carbon, extra energy is needed for the refixation of liberated equal amounts of ammonia. It is thought that the energy costs of photorespiration have an additional negative impact on crop yields in at least some environments. This paper discusses recent advances concerning the origin and evolution of photorespiration, and gives an overview of contemporary and envisioned strategies to engineer the biochemistry of, or even avoid, photorespiration.
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Structural and mechanistic aspects of carotenoid cleavage dioxygenases (CCDs).
Daruwalla, A, Kiser, PD
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2020;(11):158590
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Abstract
Carotenoid cleavage dioxygenases (CCDs) comprise a superfamily of mononuclear non-heme iron proteins that catalyze the oxygenolytic fission of alkene bonds in carotenoids to generate apocarotenoid products. Some of these enzymes exhibit additional activities such as carbon skeleton rearrangement and trans-cis isomerization. The group also includes a subfamily of enzymes that split the interphenyl alkene bond in molecules such as resveratrol and lignostilbene. CCDs are involved in numerous biological processes ranging from production of light-sensing chromophores to degradation of lignin derivatives in pulping waste sludge. These enzymes exhibit unique features that distinguish them from other families of non-heme iron enzymes. The distinctive properties and biological importance of CCDs have stimulated interest in their modes of catalysis. Recent structural, spectroscopic, and computational studies have helped clarify mechanistic aspects of CCD catalysis. Here, we review these findings emphasizing common and unique properties of CCDs that enable their variable substrate specificity and regioselectivity. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
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Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors.
Packer, M
Journal of the American Society of Nephrology : JASN. 2020;(5):907-919
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Abstract
Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.