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The AAPS Journal Nov 2017Recent findings have discovered how insufficiency of ATP-binding cassette (ABC) transporter, ABCB6, can negatively impact human health. These advances were made possible... (Review)
Review
Recent findings have discovered how insufficiency of ATP-binding cassette (ABC) transporter, ABCB6, can negatively impact human health. These advances were made possible by, first, finding that ABCB6 deficiency was the genetic basis for some severe transfusion reactions and by, second, determining that functionally impaired ABCB6 variants enhanced the severity of porphyria, i.e., diseases associated with defects in heme synthesis. ABCB6 is a broad-spectrum porphyrin transporter that is capable of both exporting and importing heme and its precursors across the plasma membrane and outer mitochondrial membrane, respectively. Biochemical studies have demonstrated that while ABCB6 influences the antioxidant system by reducing the levels of reactive oxygen species, the exact mechanism is currently unknown, though effects on heme synthesis are likely. Furthermore, it is unknown what biochemical or cellular signals determine where ABCB6 localizes in the cell. This review highlights the major recent findings on ABCB6 and focuses on details of its structure, mechanism, transport, contributions to cellular stress, and current clinical implications.
Topics: ATP-Binding Cassette Transporters; Biological Transport; Humans; Stress, Physiological
PubMed: 29192381
DOI: 10.1208/s12248-017-0165-6 -
Journal of Applied Physiology... Apr 2017We have previously predicted that the decrease in maximal oxygen uptake (V̇o) that accompanies time in microgravity reflects decrements in both convective and diffusive...
We have previously predicted that the decrease in maximal oxygen uptake (V̇o) that accompanies time in microgravity reflects decrements in both convective and diffusive O transport to the mitochondria of the contracting myocytes. The aim of this investigation was therefore to quantify the relative changes in convective O transport (Q̇o) and O diffusing capacity (Do) following long-duration spaceflight. In nine astronauts, resting hemoglobin concentration ([Hb]), V̇o, maximal cardiac output (Q̇), and differences in arterial and venous O contents ([Formula: see text]-[Formula: see text]) were obtained retrospectively for International Space Station Increments 19-33 (April 2009-November 2012). Q̇o and Do were calculated from these variables via integration of Fick's Principle of Mass Conservation and Fick's Law of Diffusion. V̇o significantly decreased from pre- to postflight (-53.9 ± 45.5%, = 0.008). The significant decrease in Q̇ (-7.8 ± 9.1%, = 0.05), despite an unchanged [Hb], resulted in a significantly decreased Q̇o (-11.4 ± 10.5%, = 0.02). Do significantly decreased from pre- to postflight by -27.5 ± 24.5% ( = 0.04), as did the peak [Formula: see text]-[Formula: see text] (-9.2 ± 7.5%, = 0.007). With the use of linear regression analysis, changes in V̇o were significantly correlated with changes in Do ( = 0.47; = 0.04). These data suggest that spaceflight decreases both convective and diffusive O transport. These results have practical implications for future long-duration space missions and highlight the need to resolve the specific mechanisms underlying these spaceflight-induced changes along the O transport pathway. Long-duration spaceflight elicited a significant decrease in maximal oxygen uptake. Given the adverse physiological adaptations to microgravity along the O transport pathway that have been reported, an integrative approach to the determinants of postflight maximal oxygen uptake is needed. We demonstrate that both convective and diffusive oxygen transport are decreased following ~6 mo International Space Station missions.
Topics: Astronauts; Biological Transport; Cardiac Output; Diffusion; Female; Hemoglobins; Humans; Male; Middle Aged; Oxygen; Oxygen Consumption; Retrospective Studies; Space Flight; Weightlessness
PubMed: 28153941
DOI: 10.1152/japplphysiol.00280.2016 -
Philosophical Transactions of the Royal... Dec 2005The NADPH oxidase is the main weapon of phagocytic white blood cells that are the first line of defence of our body against invading pathogens, and patients lacking a... (Review)
Review
The NADPH oxidase is the main weapon of phagocytic white blood cells that are the first line of defence of our body against invading pathogens, and patients lacking a functional oxidase suffer from severe and recurrent infections. The oxidase is a multisubunit enzyme complex that transports electrons from cytoplasmic NADPH to molecular oxygen in order to generate superoxide free radicals. Electron transport across the plasma membrane is electrogenic and is associated with the flux of protons through voltage-activated proton channels. Both proton and electron currents can be recorded with the patch-clamp technique, but whether the oxidase is a proton channel or a proton channel modulator remains controversial. Recently, we have used the inside-out configuration of the patch-clamp technique to record proton and electron currents in excised patches. This approach allows us to measure the oxidase activity under very controlled conditions, and has provided new information about the enzymatic activity of the oxidase and its coupling to proton channels. In this chapter I will discuss how the unique characteristics of the electron and proton currents associated with the redox activity of the NADPH oxidase have extended our knowledge about the thermodynamics and the physiological regulation of this remarkable enzyme.
Topics: Biological Transport, Active; Electron Transport; Eosinophils; Free Radicals; Humans; Membrane Potentials; Models, Molecular; NADPH Oxidases; Oxygen; Phagocytosis; Proton Pumps; Thermodynamics
PubMed: 16321802
DOI: 10.1098/rstb.2005.1769 -
American Journal of Physiology.... Apr 2014Oxygen tension is critical for follicle growth and metabolism, especially for early-stage follicles, where vascularity is limited. Its role and underlying mechanism in...
Oxygen tension is critical for follicle growth and metabolism, especially for early-stage follicles, where vascularity is limited. Its role and underlying mechanism in the in vitro activation and maturation of immature to ovulatory follicles is largely unknown. In this study, early secondary (110 μm) murine follicles were isolated and encapsulated in alginate hydrogels to replicate the in vivo environment of the growing/maturing follicle. Encapsulated follicles were cultured for 8 days at either 2.5 or 20% O2. Survival (2.6-fold) and growth (1.2-fold) were significantly higher for follicles cultured at 2.5% compared with 20% O2. Using a mouse hypoxia-signaling pathway qRT-PCR array and GeneGo Metacore analysis, we found that direct target genes of the hypoxia-activated HIF1-complex were significantly upregulated in follicles cultured for 8 days at 2.5% compared with 20% O2, including the carbohydrate transport and metabolism genes Slc2a3, Vegfa, Slc2a1, Edn1, Pgk1, Ldha, and Hmox1. Other upregulated genes included carbohydrate transporters (Slc2a1, Slc2a3, and Slc16a3) and enzymes essential for glycolysis (Pgk1, Hmox1, Hk2, Gpi1, Pfkl, Pfkp, Aldoa, Gapdh, Pgam1, Eno1, Pkm2, and Ldha). For follicles cultured at 2.5% O2, a 7.2-fold upregulation of Vegfa correlated to an 18-fold increase in VEGFA levels, and a 3.2-fold upregulation of Ldha correlated to a 4.8-fold increase in lactate levels. Both VEGFA and lactate levels were significantly higher in follicles cultured at 2.5% compared with 20% O2. Therefore, enhanced hypoxia-mediated glycolysis is essential for growth and survival of early secondary follicles and provides vital insights into improving in vitro culture conditions.
Topics: Animals; Anti-Mullerian Hormone; Biological Transport; Carbohydrate Metabolism; Cell Hypoxia; Cell Survival; Cells, Cultured; Estradiol; Female; Inhibins; Mice; Oogenesis; Ovarian Follicle; Oxygen
PubMed: 24569591
DOI: 10.1152/ajpendo.00484.2013 -
Molecular Cancer Nov 2016Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have... (Review)
Review
Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells.This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Respiration; Drug Resistance, Neoplasm; Energy Metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Membrane Transport Proteins; Mitochondria; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 27825361
DOI: 10.1186/s12943-016-0555-x -
Cellular and Molecular Life Sciences :... Sep 2014Hypoxia' or decreases in oxygen availability' results in the activation of a number of different responses at both the whole organism and the cellular level. These... (Review)
Review
Hypoxia' or decreases in oxygen availability' results in the activation of a number of different responses at both the whole organism and the cellular level. These responses include drastic changes in gene expression, which allow the organism (or cell) to cope efficiently with the stresses associated with the hypoxic insult. A major breakthrough in the understanding of the cellular response to hypoxia was the discovery of a hypoxia sensitive family of transcription factors known as the hypoxia inducible factors (HIFs). The hypoxia response mounted by the HIFs promotes cell survival and energy conservation. As such, this response has to deal with important cellular process such as cell division. In this review, the integration of oxygen sensing with the cell cycle will be discussed. HIFs, as well as other components of the hypoxia pathway, can influence cell cycle progression. The role of HIF and the cell molecular oxygen sensors in the control of the cell cycle will be reviewed.
Topics: Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Cycle; Cell Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Models, Biological; Oxygen
PubMed: 24858415
DOI: 10.1007/s00018-014-1645-9 -
BioMed Research International 2015We propose a dynamic mathematical model of tissue oxygen transport by a preexisting three-dimensional microvascular network which provides nutrients for an in situ...
We propose a dynamic mathematical model of tissue oxygen transport by a preexisting three-dimensional microvascular network which provides nutrients for an in situ cancer at the very early stage of primary microtumour growth. The expanding tumour consumes oxygen during its invasion to the surrounding tissues and cooption of host vessels. The preexisting vessel cooption, remodelling and collapse are modelled by the changes of haemodynamic conditions due to the growing tumour. A detailed computational model of oxygen transport in tumour tissue is developed by considering (a) the time-varying oxygen advection diffusion equation within the microvessel segments, (b) the oxygen flux across the vessel walls, and (c) the oxygen diffusion and consumption within the tumour and surrounding healthy tissue. The results show the oxygen concentration distribution at different time points of early tumour growth. In addition, the influence of preexisting vessel density on the oxygen transport has been discussed. The proposed model not only provides a quantitative approach for investigating the interactions between tumour growth and oxygen delivery, but also is extendable to model other molecules or chemotherapeutic drug transport in the future study.
Topics: Biological Transport; Computer Simulation; Diffusion; Hemodynamics; Humans; Microvessels; Models, Theoretical; Neoplasms; Neovascularization, Pathologic; Oxygen
PubMed: 25695084
DOI: 10.1155/2015/476964 -
Biochemistry Nov 2021Iron is an essential nutrient for virtually every living organism, especially pathogenic prokaryotes. Despite its importance, however, both the acquisition and the... (Review)
Review
Iron is an essential nutrient for virtually every living organism, especially pathogenic prokaryotes. Despite its importance, however, both the acquisition and the export of this element require dedicated pathways that are dependent on oxidation state. Due to its solubility and kinetic lability, reduced ferrous iron (Fe) is useful to bacteria for import, chaperoning, and efflux. Once imported, ferrous iron may be loaded into apo and nascent enzymes and even sequestered into storage proteins under certain conditions. However, excess labile ferrous iron can impart toxicity as it may spuriously catalyze Fenton chemistry, thereby generating reactive oxygen species and leading to cellular damage. In response, it is becoming increasingly evident that bacteria have evolved Fe efflux pumps to deal with conditions of ferrous iron excess and to prevent intracellular oxidative stress. In this work, we highlight recent structural and mechanistic advancements in our understanding of prokaryotic ferrous iron import and export systems, with a focus on the connection of these essential transport systems to pathogenesis. Given the connection of these pathways to the virulence of many increasingly antibiotic resistant bacterial strains, a greater understanding of the mechanistic details of ferrous iron cycling in pathogens could illuminate new pathways for future therapeutic developments.
Topics: Anti-Bacterial Agents; Bacteria; Biological Transport; Catalysis; Homeostasis; Ion Transport; Iron; Kinetics; Membrane Proteins; Membrane Transport Proteins; Oxidation-Reduction; Oxidative Stress; Prokaryotic Cells; Reactive Oxygen Species; Solubility; Virulence
PubMed: 34670078
DOI: 10.1021/acs.biochem.1c00586 -
The Journal of Biological Chemistry Feb 2022Hypoxia exerts profound effects on cell physiology, but its effect on colonic uptake of the microbiota-generated forms of vitamin B1 (i.e., thiamin pyrophosphate [TPP]...
Hypoxia exerts profound effects on cell physiology, but its effect on colonic uptake of the microbiota-generated forms of vitamin B1 (i.e., thiamin pyrophosphate [TPP] and free thiamine) has not been described. Here, we used human colonic epithelial NCM460 cells and human differentiated colonoid monolayers as in vitro and ex vivo models, respectively, and were subjected to either chamber (1% O, 5% CO, and 94% N) or chemically (desferrioxamine; 250 μM)-induced hypoxia followed by determination of different physiological-molecular parameters. We showed that hypoxia causes significant inhibition in TPP and free thiamin uptake by colonic NCM460 cells and colonoid monolayers; it also caused a significant reduction in the expression of TPP (SLC44A4) and free thiamin (SLC19A2 and SLC19A3) transporters and in activity of their gene promoters. Furthermore, hypoxia caused a significant induction in levels of hypoxia-inducible transcription factor (HIF)-1α but not HIF-2α. Knocking down HIF-1α using gene-specific siRNAs in NCM460 cells maintained under hypoxic conditions, on the other hand, led to a significant reversal in the inhibitory effect of hypoxia on TPP and free thiamin uptake as well as on the expression of their transporters. Finally, a marked reduction in level of expression of the nuclear factors cAMP responsive element-binding protein 1 and gut-enriched Krüppel-like factor 4 (required for activity of SLC44A4 and SLC19A2 promoters, respectively) was observed under hypoxic conditions. In summary, hypoxia causes severe inhibition in colonic TPP and free thiamin uptake that is mediated at least in part via HIF-1α-mediated transcriptional mechanisms affecting their respective transporters.
Topics: Biological Transport; Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Transport Proteins; Microbiota; Thiamine; Thiamine Pyrophosphate
PubMed: 34998824
DOI: 10.1016/j.jbc.2022.101562 -
Biochimica Et Biophysica Acta May 2011Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and... (Review)
Review
Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
Topics: Absorption; Animals; Biological Transport; Heme; Heme Oxygenase (Decyclizing); Humans; Intracellular Space; Membrane Transport Proteins
PubMed: 21238504
DOI: 10.1016/j.bbamcr.2011.01.008