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Keyword: hypoxia
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Articles
Biochem Soc Trans (2018) 46 (3): 599-607.
Published: 20 April 2018
...Andrew J. Murray; Hugh E. Montgomery; Martin Feelisch; Michael P.W. Grocott; Daniel S. Martin Ascent to high altitude is associated with physiological responses that counter the stress of hypobaric hypoxia by increasing oxygen delivery and by altering tissue oxygen utilisation via metabolic...
Abstract
Ascent to high altitude is associated with physiological responses that counter the stress of hypobaric hypoxia by increasing oxygen delivery and by altering tissue oxygen utilisation via metabolic modulation. At the cellular level, the transcriptional response to hypoxia is mediated by the hypoxia-inducible factor (HIF) pathway and results in promotion of glycolytic capacity and suppression of oxidative metabolism. In Tibetan highlanders, gene variants encoding components of the HIF pathway have undergone selection and are associated with adaptive phenotypic changes, including suppression of erythropoiesis and increased blood lactate levels. In some highland populations, there has also been a selection of variants in PPARA , encoding peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional regulator of fatty acid metabolism. In one such population, the Sherpas, lower muscle PPARA expression is associated with a decreased capacity for fatty acid oxidation, potentially improving the efficiency of oxygen utilisation. In lowlanders ascending to altitude, a similar suppression of fatty acid oxidation occurs, although the underlying molecular mechanism appears to differ along with the consequences. Unlike lowlanders, Sherpas appear to be protected against oxidative stress and the accumulation of intramuscular lipid intermediates at altitude. Moreover, Sherpas are able to defend muscle ATP and phosphocreatine levels in the face of decreased oxygen delivery, possibly due to suppression of ATP demand pathways. The molecular mechanisms allowing Sherpas to successfully live, work and reproduce at altitude may hold the key to novel therapeutic strategies for the treatment of diseases to which hypoxia is a fundamental contributor.
Articles
Biochem Soc Trans (2016) 44 (4): 1111-1116.
Published: 15 August 2016
... Biochemical Society 2016 cancer metabolism fumarate hydratase hypoxia isocitrate dehydrogenase reactive oxygen species (ROS) succinate dehydrogenase Metabolic reprogramming is now a recognized hallmark of cancer transformation. The first observation of this phenotype was in the early 1920s...
Abstract
In the early 1920s Otto Warburg observed that cancer cells have altered metabolism and from this, posited that mitochondrial dysfunction underpinned the aetiology of cancers. The more recent identification of mutations of mitochondrial metabolic enzymes in a wide range of human cancers has now provided a direct link between metabolic alterations and cancer. In this review we discuss the consequences of dysfunction of three metabolic enzymes involved in or associated with the tricarboxylic acid (TCA) cycle: succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) focusing on the similarity between the phenotypes of cancers harbouring these mutations.
Articles
Biochem Soc Trans (2014) 42 (2): 457-460.
Published: 20 March 2014
...) glycation hypoxia proteostasis unfolded protein response (UPR) Protein homoeostasis, or proteostasis, is conducted through sophisticated networks of mechanisms to maintain the quality of proteins. The quality control of proteins is carefully regulated by the balance of protein synthesis, folding...
Abstract
Glycation is one of the important reactions regulating physiological state, and glycative stress, namely an overwhelming and unfavourable glycation state, is established as a pathological factor. Glycative stress is closely associated with not only various kidney diseases, but also kidney aging. Accumulating evidence, including studies in my laboratory, demonstrates that progression of renal tubular damage and its aging is correlated with the decrease in the activity of anti-glycative stress enzyme Glo1 (glyoxalase I) in the kidney. The reduction of glycative and oxidative stresses by Glo1 overexpression is beneficial for prevention of kidney disease and treatment, suggesting the novel therapeutic approaches targeting Glo1. The present review is focused on the impact of glycative stress and Glo1 on protein homoeostasis and discusses further the cross-talk between glycative stress and UPR (unfolded protein response), which controls the protein homoeostasis state.
Articles
Biochem Soc Trans (2013) 41 (5): 1325-1330.
Published: 23 September 2013
...) mitochondrial complex I hypoxia ischaemia thiol modification thiol nitrosation Production of energy in most aerobic cells is provided by the combined action of the mitochondrial respiratory chain and ATP synthase. Reducing equivalents from pyridine nucleotides (NADH) generated in several catabolic...
Abstract
The unique feature of mitochondrial complex I is the so-called A/D transition (active–deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone ( k ~10 4 min −1 ) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow ( k ~1–10 min −1 ) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys 39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.
Articles
Biochem Soc Trans (2013) 41 (2): 657-663.
Published: 21 March 2013
...Colin R. Lenihan; Cormac T. Taylor Hypoxia is a frequently encountered feature of the cellular microenvironment in a number of pathophysiological processes in which programmed cell death (apoptosis) affects disease progression including, but not limited to, cancer, chronic inflammation, myocardial...
Abstract
Hypoxia is a frequently encountered feature of the cellular microenvironment in a number of pathophysiological processes in which programmed cell death (apoptosis) affects disease progression including, but not limited to, cancer, chronic inflammation, myocardial infarction, stroke and ischaemic acute kidney injury. In these diseases, the presence of hypoxia can significantly affect the rate of cell death and thus may make a significant contribution to disease progression. In the present review, we discuss the complex relationship that exists between the presence of hypoxia and the regulation of cell death pathways.
Articles
Biochem Soc Trans (2013) 41 (1): 273-276.
Published: 29 January 2013
...@med.lu.se ). 21 9 2012 © The Authors Journal compilation © 2013 Biochemical Society 2013 angiogenesis cancer coagulation exosome hypoxia microvesicle The preceding view of intercellular communication in mammalian organisms has been limited to direct cell–cell contact, the...
Abstract
Over the last few decades, extensive studies by several groups have introduced the concept of cell-derived secreted extracellular membrane vesicles as carriers of complex molecular information. Owing to their pleiotropic biological effects and involvement in a wide variety of biological processes, extracellular membrane vesicles have been implicated in physiological as well as pathological events, including tumour development and metastasis. In the present review, we discuss the role of secreted membrane vesicles in intercellular communication with a focus on tumour biology. Of particular interest is the potential role of extracellular vesicles as orchestrators of common features of the malignant tumour microenvironment, e.g. coagulation activation and angiogenesis.
Articles
Biochem Soc Trans (2011) 39 (6): 1556-1559.
Published: 21 November 2011
... capillarity by more than 50%, (ii) decreases exercise endurance time by approximately 80%, and (iii) abolishes the angiogenic response to exercise training. What causes VEGF to increase with exercise is not clear. Despite regulation by HIF (hypoxia-inducible factor), increased HIF on exercise, and P O 2...
Abstract
VEGF (vascular endothelial growth factor) is well known as an important molecule in angiogenesis. Its inhibition is pursued as an anticancer therapy; its enhancement as therapy for tissue ischaemia. In the present paper, its role in skeletal muscle is explored, both at rest and after exercise. Muscle VEGF mRNA and protein are increased severalfold after heavy exercise. Whereas global VEGF knockout is embryonically lethal, muscle-specific knockout is not, providing models for studying its functional significance. Its deletion in adult mouse skeletal muscle: (i) reduces muscle capillarity by more than 50%, (ii) decreases exercise endurance time by approximately 80%, and (iii) abolishes the angiogenic response to exercise training. What causes VEGF to increase with exercise is not clear. Despite regulation by HIF (hypoxia-inducible factor), increased HIF on exercise, and P O 2 falling to single digit values during exercise, muscle-specific HIF knockout does not impair performance or capillarity, leaving many unanswered questions.
Articles
Biochem Soc Trans (2009) 37 (6): 1221-1227.
Published: 19 November 2009
... compilation © 2009 Biochemical Society 2009 hypoxia ischaemic disease Notch intracellular domain Notch signalling therapeutic angiogenesis vascular endothelial growth factor (VEGF) In the Western world, ischaemic disease is highly prevalent and is associated with elevated morbidity and...
Abstract
Notch signalling represents a key pathway essential for normal vascular development. Recently, great attention has been focused on the implication of Notch pathway components in postnatal angiogenesis and regenerative medicine. This paper critically reviews the most recent findings supporting the role of Notch in ischaemia-induced neovascularization. Notch signalling reportedly regulates several steps of the reparative process occurring in ischaemic tissues, including sprouting angiogenesis, vessel maturation, interaction of vascular cells with recruited leucocytes and skeletal myocyte regeneration. Further characterization of Notch interaction with other signalling pathways might help identify novel targets for therapeutic angiogenesis.
Articles
Biochem Soc Trans (2009) 37 (1): 284-288.
Published: 20 January 2009
... should be addressed (email megan.cully@cancer.org.uk ). 23 9 2008 © The Authors Journal compilation © 2009 Biochemical Society 2009 eukaryotic elongation factor 2 kinase (eEF2k) eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hypoxia mammalian target of rapamycin (mTOR...
Abstract
Cellular stresses can induce a wide range of biological responses, depending on the type of stress, the type of cell and the cellular environment. Stress-mediated changes in translational output cover a broad spectrum of potential responses, including an overall decrease in translation or an increase in the translation of specific mRNAs. Many of these changes involve post-translational modifications of components of the translational machinery. The mTOR (mammalian target of rapamycin) pathway is a critical regulator of growth and translation in response to a wide variety of signals, including growth factors, amino acids and energy availability. Through its kinase activity, mTOR activation results in the phosphorylation of translational components and an increase in translation. As stress-mediated changes in translational output are context-dependent, the interplay between stress and mTOR in the control of translation is also likely to depend on factors such as the strength and type of incident stress. In the present paper, we review mTOR-dependent and -independent translational responses, and discuss their regulation by stress.
Articles
Biochem Soc Trans (2008) 36 (3): 445-448.
Published: 21 May 2008
... deprivation (hypoxia). Here, we will briefly review the evolving evidence for this pathway in the regulation of a number of metabolic regulators and discuss a possible role for SUMOylation in the regulation of basic metabolic function. 1 To whom correspondence should be addressed (email cormac.taylor...
Abstract
Post-translational modification is a critical event in the dynamic regulation of protein stability, location, structure, function, activity and interaction with other proteins and as such plays an important role in organism complexity. Over the last 10 years, the extensive and critical role of one such protein modification by SUMO (small ubiquitin-related modifier) has become apparent. The focus of this mini-review will be on recent reports of a possible functional role for the SUMO pathway in the adaptive cellular response to metabolic challenge, such as oxygen deprivation (hypoxia). Here, we will briefly review the evolving evidence for this pathway in the regulation of a number of metabolic regulators and discuss a possible role for SUMOylation in the regulation of basic metabolic function.
Articles
Biochem Soc Trans (2007) 35 (5): 905-907.
Published: 25 October 2007
..., University of Leeds, Leeds LS2 9JT, U.K. (email medkep@leeds.ac.uk ). 15 6 2007 © The Authors Journal compilation © 2007 Biochemical Society 2007 cardiac fibroblast collagen hypoxia invasion matrix metalloproteinase (MMP) myocardial remodelling The adult heart consists of...
Abstract
Cardiac fibroblasts account for up to two-thirds of the total number of cells in the normal heart and are responsible for extracellular matrix homoeostasis. In vitro , type I collagen, the predominant myocardial collagen, stimulates proteolytic activation of constitutively secreted proMMP-2 (pro-matrix metalloproteinase-2). This occurs at the cell membrane and requires formation of a ternary complex with MT1-MMP (membrane-type-1 MMP) and TIMP-2 (tissue inhibitor of metalloproteinases-2). Following MI (myocardial infarction), normally quiescent fibroblasts initiate a wound healing response by transforming into a proliferative and invasive myofibroblast phenotype. Deprivation of oxygen to the myocardium is an inevitable consequence of MI; therefore this reparative event occurs under chronically hypoxic conditions. However, species and preparation variations can strongly influence fibroblast behaviour, which is an important consideration when selecting experimental models for provision of clinically useful information.
Articles
Biochem Soc Trans (2005) 33 (6): 1394-1396.
Published: 26 October 2005
... factors including, particularly oxygen, superoxide, H 2 O 2 , antioxidants, thiols and glycolysis. 1 To whom correspondence should be addressed (email vb207@mole.bio.cam.ac.uk ). 4 7 2005 © 2005 The Biochemical Society 2005 apoptosis hypoxia necrosis nitric oxide (NO...
Abstract
Nitric oxide (NO) can induce cell death; however, NO-induced cell death may be dependent/conditional on factors other than NO itself. Whether NO kills a particular cell depends on the amount of NO, source of NO, time of exposure to NO, cell type and the levels of other factors including, particularly oxygen, superoxide, H 2 O 2 , antioxidants, thiols and glycolysis.
Articles
Biochem Soc Trans (2005) 33 (5): 1078-1081.
Published: 26 October 2005
... p.trayhurn@liverpool.ac.uk ). 11 7 2005 © 2005 The Biochemical Society 2005 adipokine adipose tissue cytokine hypoxia inflammation metabolic syndrome White adipose tissue (WAT) has become the subject of considerable activity in recent years and is now a ‘hot spot’ in...
Abstract
White adipose tissue (WAT) is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. A number of adipokines, including leptin, adiponectin, tumour necrosis factor α, IL-1β (interleukin 1β), IL-6, monocyte chemotactic protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands (adiponectin, which has anti-inflammatory action is an exception). The elevated production of inflammation-related adipokines is increasingly considered to be important in the development of diseases linked to obesity, particularly Type II diabetes and the metabolic syndrome. WAT is involved in extensive cross-talk with other organs and multiple metabolic systems through the various adipokines.
Articles
Biochem Soc Trans (2005) 33 (5): 1137-1139.
Published: 26 October 2005
...L. Callinan; T.V. McCarthy; Y. Maulet; J.J. Mackrill One type of cellular response to hypoxia is an increase in cytosolic Ca 2+ . VDCCs (voltage-dependent calcium channels) open upon membrane depolarization allowing inward current of Ca 2+ ions. Two of the so-called L-type VDCC α1 subunits, Ca v...
Abstract
One type of cellular response to hypoxia is an increase in cytosolic Ca 2+ . VDCCs (voltage-dependent calcium channels) open upon membrane depolarization allowing inward current of Ca 2+ ions. Two of the so-called L-type VDCC α1 subunits, Ca v 1.2 and Ca v 1.3, are found in the brain. We sought to investigate the effect of chronic hypoxia or treatment with a hypoxia-mimicking agent DFX (desferrioxamine mesylate) on expression of L-type VDCC in the SH-SY5Y neuroblastoma cell line. Western blotting identified two atypical forms of the L-type channel with apparent molecular masses of approx. 100 and 150 kDa, compared with typical forms of approx. 200 kDa. Immunofluorescence microscopy shows the approx. 100 kDa protein located within the cell and on the cell surface, while the approx. 150 kDa protein is intracellular with punctate staining. Further analysis revealed that this approx. 150 kDa protein co-localizes with nuclear proteins but not with markers for other intracellular compartments. In addition, these proteins are both down-regulated in DFX-treated and hypoxic cells, suggesting that the mechanism of down-regulation is along the HIF (hypoxia-inducible factor) pathway. This atypical localization of the 150 kDa protein suggests that it might play a role in nuclear calcium signalling in health and disease.
Articles
Biochem Soc Trans (2004) 32 (6): 1068-1069.
Published: 26 October 2004
... inducible NOS (nitric oxide synthase) highly sensitizes neurons to hypoxia-induced death, probably via the NO–oxygen competition at cytochrome oxidase. Thus the NO from neuronal NOS during excitotoxicity or the NO from inducible NOS during inflammation may sensitize the brain to hypoxic/ischaemic damage...
Abstract
NO (nitric oxide) acutely and potently inhibits mitochondrial cytochrome oxidase in competition with oxygen, thereby raising the apparent K M for oxygen of mitochondria and neurons into the physiological or pathological range. We find that NO from an NO donor or glial inducible NOS (nitric oxide synthase) highly sensitizes neurons to hypoxia-induced death, probably via the NO–oxygen competition at cytochrome oxidase. Thus the NO from neuronal NOS during excitotoxicity or the NO from inducible NOS during inflammation may sensitize the brain to hypoxic/ischaemic damage.
Articles
Biochem Soc Trans (2004) 32 (6): 943-945.
Published: 26 October 2004
...D.E. Lancaster; M.A. McDonough; C.J. Schofield FIH (Factor inhibiting hypoxia-inducible factor), an asparaginyl β-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of hypoxia-inducible factor, a transcription factor...
Abstract
FIH (Factor inhibiting hypoxia-inducible factor), an asparaginyl β-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of hypoxia-inducible factor, a transcription factor that regulates the mammalian hypoxic response. Only one other asparaginyl β-hydroxylase, which catalyses hydroxylation of both aspartyl and asparaginyl residues in EGF (epidermal growth factor)-like domains, has been characterized. In the light of recent crystal structures of FIH, we compare FIH with the EGFH (EGF β-hydroxylase) and putative asparagine/asparaginyl hydroxylases. Sequence analyses imply that EGFH does not contain the HXD/E iron-binding motif characteristic of most of the 2-oxoglutarate oxygenases.
Articles
Biochem Soc Trans (2003) 31 (3): 510-515.
Published: 01 June 2003
...K.S. Hewitson; L.A. McNeill; J.M. Elkins; C.J. Schofield Sensing of ambient dioxygen levels and appropriate feedback mechanisms are essential processes for all multicellular organisms. In animals, moderate hypoxia causes an increase in the transcription levels of specific genes, including those...
Abstract
Sensing of ambient dioxygen levels and appropriate feedback mechanisms are essential processes for all multicellular organisms. In animals, moderate hypoxia causes an increase in the transcription levels of specific genes, including those encoding vascular endothelial growth factor and erythropoietin. The hypoxic response is mediated by hypoxia-inducible factor (HIF), an αβ heterodimeric transcription factor in which both the HIF subunits are members of the basic helix–loop–helix PAS (PER-ARNT-SIM) domain family. Under hypoxic conditions, levels of HIFα rise, allowing dimerization with HIFβ and initiating transcriptional activation. Two types of dioxygen-dependent modification to HIFα have been identified, both of which inhibit the transcriptional response. Firstly, HIFα undergoes trans -4-hydroxylation at two conserved proline residues that enable its recognition by the von Hippel-Lindau tumour-suppressor protein. Subsequent ubiquitinylation, mediated by an ubiquitin ligase complex, targets HIFα for degradation. Secondly, hydroxylation of an asparagine residue in the C-terminal transactivation domain of HIFα directly prevents its interaction with the co-activator p300. Hydroxylation of HIFα is catalysed by enzymes of the iron(II)- and 2-oxoglutarate-dependent dioxygenase family. In humans, three prolyl hydroxylase isoenzymes (PHD1–3) and an asparagine hydroxylase [factor inhibiting HIF (FIH)] have been identified. The role of 2-oxoglutarate oxygenases in the hypoxic and other signalling pathways is discussed.
Articles
Biochem Soc Trans (2001) 29 (2): 86-90.
Published: 01 May 2001
... fetal growth retardation placenta pre-eclampsia perfusion hypoxia CNS, central nervous system hCG, human chorionic gonadotropin hPL, human placental lactogen IUGR, intra-uterine growth retardation Biochemical Society Transactions (200 I) Volume 29, part 2 Physiological and pathological...
Abstract
There is clear evidence of placental leptin production, as shown recently in trophoblast cultures and by dual in vitro placenta perfusion (median production of 225 pg/min per g of tissue; 98.4% released into the maternal and 1.6% into the fetal circulation). However, the physiological impact for the mother and the fetus is unclear. The classical role of leptin is to provide information about energy stores to the central nervous system, and to reduce appetite if the energy stores are full. In pregnancy, maternal plasma leptin concentrations are elevated, and lack the well established correlation with body fat energy stores that is observed in non-pregnant women, indicating an alternative function for leptin during pregnancy and fetal development. Maternal and fetal plasma leptin levels are dysregulated in pathological conditions such as gestational diabetes, pre-eclampsia and intra-uterine growth retardation, representing an effect or a cause of disturbances in the feto/placento/maternal unit.
Articles
Biochem Soc Trans (2001) 29 (2): 42-48.
Published: 01 May 2001
...-mail Russ.Anthony@Colostate.edu ) 13 12 2000 © 2001 Biochemical Society 2001 angiogenesis hypoxia intrauterine growth restriction placental lactogen transcription Ang, angiopoietin AP, activator protein bHLH, basis helix-loop-helix CSEn, chorionic somatomammotropin gene...
Abstract
The placenta synthesizes a number of cytokines and growth factors that are involved in the establishment, maintenance or regulation of pregnancy. Included are interferons, placental lactogens, other members of the growth hormone/prolactin gene family, leptin, and an array of angiogenic growth factors. While their roles in pregnancy differ, in their absence pregnancy is either lost or compromised. Therefore an understanding of the cell-specific transcriptional regulation of these genes is imperative if we are ever to alter their expression to benefit pregnancy progression. Our understanding of transcriptional regulation in the placenta is still in its infancy, and there appears to be considerable divergence in the transcriptional regulation of these genes between species, as well as between the various cytokine genes being examined. For example, while there are some commonalities in the regulation of human, rodent and ruminant placental lactogens, there are differences that require the study of placental lactogen gene regulation across species. However, one common theme that is emerging with the angiogenic growth factors, such as vascular endothelial growth factor and the angio-poietins, is the transcriptional control of these genes by oxygen tension within the placenta. Examination of transcriptional regulation in normal and compromised pregnancies will provide additional insight in this area.