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krebs cycle

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https://www.readbyqxmd.com/read/28104508/exposure-to-high-levels-of-fumarate-and-succinate-leads-to-apoptotic-cytotoxicity-and-altered-global-dna-methylation-profiles-in-vitro
#1
Johannes F Wentzel, Angélique Lewies, Abel J Bronkhorst, Etresia van Dyk, Lissinda H du Plessis, Piet J Pretorius
In the Krebs cycle, succinate is oxidized to fumarate by succinate dehydrogenase (SDH), followed by the conversion of fumarate to malate by fumarate hydratase (FH). In cells with defective SDH and FH, the Krebs cycle is congested, respiration impaired and fumarate and succinate accumulates. Several studies have indicated that the accumulation of these substrates are associated with cytotoxicity and oncogenesis. High levels of succinate and fumarate induce hypoxia inducible factor (HIF1A) hydroxylases, leading to the activation of oncogenic HIF pathways...
January 16, 2017: Biochimie
https://www.readbyqxmd.com/read/28100843/pathophysiology-and-molecular-basis-of-selected-metabolic-abnormalities-in-huntington-s-disease
#2
Jolanta Krzysztoń-Russjan
Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed...
December 30, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28098230/molecular-mechanism-of-the-allosteric-regulation-of-the-%C3%AE-%C3%AE-heterodimer-of-human-nad-dependent-isocitrate-dehydrogenase
#3
Tengfei Ma, Yingjie Peng, Wei Huang, Jianping Ding
Human NAD-dependent isocitrate dehydrogenase catalyzes the decarboxylation of isocitrate (ICT) into α-ketoglutarate in the Krebs cycle. It exists as the α2βγ heterotetramer composed of the αβ and αγ heterodimers. Previously, we have demonstrated biochemically that the α2βγ heterotetramer and αγ heterodimer can be allosterically activated by citrate (CIT) and ADP. In this work, we report the crystal structures of the αγ heterodimer with the γ subunit bound without or with different activators...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28075562/evidence-for-a-di-%C3%A2%C2%B5-oxo-diamond-core-in-the-mn-iv-fe-iv-activation-intermediate-of-ribonucleotide-reductase-from-chlamydia-trachomatis
#4
Ryan J Martinie, Elizabeth J Blaesi, Carsten Krebs, J Martin Bollinger, Alexey Silakov, Christopher J Pollock
High-valent iron and manganese complexes effect some of the most challenging biochemical reactions known, including hydrocarbon and water oxidations associated with the global carbon cycle and oxygenic photosynthesis, respectively. Their extreme reactivity presents an impediment to structural characterization, but their biological importance and potential chemical utility have, nevertheless, motivated extensive efforts toward that end. Several such intermediates accumulate during activation of class I ribonucleotide reductase (RNR) β subunits, which self-assemble dimetal cofactors with stable one-electron oxidants that serve to initiate the enzyme's free-radical mechanism...
January 11, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28073690/citrate-pathophysiology-and-metabolism
#5
REVIEW
Mehran Monchi
By chelating ionized calcium, citrate allows extracorporeal circuit anticoagulation without a bleeding risk for the patient. Citrate anticoagulation is also associated with a reduced activation of leucocytes and platelets. Citrate clearance by citric acid cycle (Krebs cycle) is not modified by renal failure, but is reduced by about 50% in patients with cirrhosis. Toxic effects of citrate result from a decrease in plasma ionized calcium of the patient. The first side effect is a prolongation of the QT interval...
December 30, 2016: Transfusion and Apheresis Science
https://www.readbyqxmd.com/read/28070280/surviving-winter-food-but-not-habitat-structure-prevents-crashes-in-cyclic-vole-populations
#6
Kaja Johnsen, Rudy Boonstra, Stan Boutin, Olivier Devineau, Charles J Krebs, Harry P Andreassen
Vole population cycles are a major force driving boreal ecosystem dynamics in northwestern Eurasia. However, our understanding of the impact of winter on these cycles is increasingly uncertain, especially because climate change is affecting snow predictability, quality, and abundance. We examined the role of winter weather and snow conditions, the lack of suitable habitat structure during freeze-thaw periods, and the lack of sufficient food as potential causes for winter population crashes. We live-trapped bank voles Myodes glareolus on 26 plots (0...
January 2017: Ecology and Evolution
https://www.readbyqxmd.com/read/28069660/antioxidant-treatment-attenuates-lactate-production-in-diabetic-nephropathy
#7
Christoffer Laustsen, Per Mose Nielsen, Thomas Stokholm Nørlinger, Haiyun Qi, Uffe Kjærgaard Pedersen, Lotte Bonde Bertelsen, Jakob Appel Østergaard, Allan Flyvbjerg, Jan Henrik Ardenkjær-Larsen, Fredrik Palm, Hans Stødkilde-Jørgensen
The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-(13)C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging...
January 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28067713/widespread-down-regulation-of-cardiac-mitochondrial-and-sarcomeric-genes-in-patients-with-sepsis
#8
Scot J Matkovich, Belal Al Khiami, Igor R Efimov, Sarah Evans, Justin Vader, Ashwin Jain, Bernard H Brownstein, Richard S Hotchkiss, Douglas L Mann
OBJECTIVES: The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts. DESIGN: Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts. SETTING: ICUs at Barnes-Jewish Hospital, St...
January 6, 2017: Critical Care Medicine
https://www.readbyqxmd.com/read/28059791/mitochondrial-repair-effects-of-oxygen-treatment-on-alzheimer-s-disease-model-mice-revealed-by-quantitative-proteomics
#9
Hao Wang, Xiaoyu Hong, Yong Wang
Mitochondrial dysfunction plays a pivotal role in Alzheimer's disease (AD), even before signs of AD pathology are evident. Our previous research has shown that oxygen treatment can improve cognitive function in AD model mice. To address whether oxygen treatment is beneficial to mitochondrial biology, we analyzed differential expressions of hippocampal mitochondrial proteins in AD model mice given supplementary oxygen. Numerous respiratory chain, Kreb's cycle, and glycolysis proteins were upregulated significantly after oxygen treatment, suggesting that oxygen therapy can alleviate mitochondrial damage...
December 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28043145/cytotoxic-effect-of-oxaloacetate-on-hepg2-human-hepatic-carcinoma-cells-via-apoptosis-and-ros-accumulation
#10
Y Jiao, L Ji, Y Kuang, Q Yang
Oxaloacetate (OA) is one of the intermediates of the Krebs cycle. In addition to its role in energy production, OA may have other effects on the cell. We report here that OA could have a cell type dependent cytotoxic effect on the human hepatic carcinoma cell line HepG2 through induction of apoptosis and reactive oxygen species (ROS) accumulation. In our study, OA decreased the viability and colony formation of HepG2 cells and induced cell death. Caspase-3 activity was increased, the pro-apoptotic protein Bax was up-regulated, and the anti-apoptotic protein Bcl-2 was down-regulated in OA-treated HepG2 cells indicating that apoptosis through the intrinsic pathway was involved in the cell death...
January 3, 2017: Neoplasma
https://www.readbyqxmd.com/read/28025847/metabolic-remodeling-triggered-by-salivation-and-diabetes-in-major-salivary-glands
#11
Fernando N Nogueira, Rui A Carvalho
The metabolic profile of major salivary glands was evaluated by (13) C nuclear magnetic resonance isotopomer analysis ((13) C NMR-IA) following the infusion of [U-(13) C]glucose in order to define the true metabolic character of submandibular (SM) and parotid (PA) glands at rest and during salivary stimulation, and to determine the metabolic remodeling driven by diabetes. In healthy conditions, the SM gland is characterized at rest by a glycolytic metabolic profile and extensive pyruvate cycling. On the contrary, the PA gland, although also dominated by glycolysis, also possesses significant Krebs' cycle activity and does not sustain extensive pyruvate cycling...
December 26, 2016: NMR in Biomedicine
https://www.readbyqxmd.com/read/28017777/the-cardioprotective-effect-of-sildenafil-is-mediated-by-the-activation-of-malate-dehydrogenase-and-an-increase-in-the-malate-aspartate-shuttle-in-cardiomyocytes
#12
Gevi Federica, Campolo Federica, Naro Fabio, Zolla Lello
Recent evidence has shown showed the cardioprotective effect of PDE5 inhibition in myocardial ischemia/reperfusion injury, heart failure and cardiac hypertrophy. To investigate the biochemical changes that occur during PDE5 inhibition in cardiac cells, this study assessed the metabolic profile of the HL1 cell line, a murine atrial cell line with adult cardiomyocyte properties. After one hour of treatment with sildenafil, glycolysis was moderately but selectively stimulated, unlike the pentose phosphate pathway and the Krebs cycle...
December 22, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28017472/loss-of-nardilysin-a-mitochondrial-co-chaperone-for-%C3%AE-ketoglutarate-dehydrogenase-promotes-mtorc1-activation-and-neurodegeneration
#13
Wan Hee Yoon, Hector Sandoval, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Shinya Yamamoto, Nele A Haelterman, Nagireddy Putluri, Vasanta Putluri, Arun Sreekumar, Tulay Tos, Ayse Aksoy, Taraka Donti, Brett H Graham, Mikiko Ohno, Eiichiro Nishi, Jill Hunter, Donna M Muzny, Jason Carmichael, Joseph Shen, Valerie A Arboleda, Stanley F Nelson, Michael F Wangler, Ender Karaca, James R Lupski, Hugo J Bellen
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy...
January 4, 2017: Neuron
https://www.readbyqxmd.com/read/27989324/mutations-in-mdh2-encoding-a-krebs-cycle-enzyme-cause-early-onset-severe-encephalopathy
#14
Samira Ait-El-Mkadem, Manal Dayem-Quere, Mirjana Gusic, Annabelle Chaussenot, Sylvie Bannwarth, Bérengère François, Emmanuelle C Genin, Konstantina Fragaki, Catharina L M Volker-Touw, Christelle Vasnier, Valérie Serre, Koen L I van Gassen, Françoise Lespinasse, Susan Richter, Graeme Eisenhofer, Cécile Rouzier, Fanny Mochel, Anne De Saint-Martin, Marie-Thérèse Abi Warde, Monique G M de Sain-van der Velde, Judith J M Jans, Jeanne Amiel, Ziga Avsec, Christian Mertes, Tobias B Haack, Tim Strom, Thomas Meitinger, Penelope E Bonnen, Robert W Taylor, Julien Gagneur, Peter M van Hasselt, Agnès Rötig, Agnès Delahodde, Holger Prokisch, Sabine A Fuchs, Véronique Paquis-Flucklinger
MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null...
January 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27984134/long-title-translational-potential-of-long-term-decreases-in-mitochondrial-lipids-in-a-mouse-model-of-gulf-war-illness
#15
Laila Abdullah, James E Evans, Utsav Joshi, Gogce Crynen, John Reed, Benoit Mouzon, Stephan Baumann, Hannah Montague, Zuchra Zakirova, Tanja Emmerich, Corbin Bachmeier, Nancy Klimas, Kimberly Sullivan, Michael Mullan, Ghania Ait-Ghezala, Fiona Crawford
Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10days to GW agents (pyridostigmine bromide and permethrin)...
October 29, 2016: Toxicology
https://www.readbyqxmd.com/read/27959577/hyperosmotic-environment-blunts-effectivity-of-ischemic-preconditioning-against-ischemia-reperfusion-injury-and-improves-ischemic-tolerance-in-non-preconditioned-isolated-rat-hearts
#16
M Zálešák, P BlaŽíček, D Pancza, I Gablovský, V Štrbák, T Ravingerová
Several studies have shown that diabetes mellitus modulates heart resistance to ischemia and abrogates effectivity of cardioprotective interventions, such as ischemic preconditioning (IP). The aim of this study was to evaluate whether the effect of hyperglycemic conditions on the severity of ischemia-reperfusion (I/R) injury in preconditioned and non-preconditioned hearts (controls, C) is related to changes in osmotic activity of glucose. Experiments were performed in isolated rat hearts perfused according to Langendorff exposed to 30-min coronary occlusion/120-min reperfusion...
December 13, 2016: Physiological Research
https://www.readbyqxmd.com/read/27958316/the-key-role-of-meteorites-in-the-formation-of-relevant-prebiotic-molecules-in-a-formamide-water-environment
#17
Luca Rotelli, Josep M Trigo-Rodríguez, Carles E Moyano-Cambero, Eleonora Carota, Lorenzo Botta, Ernesto Di Mauro, Raffaele Saladino
We show that carbonaceous chondrite meteorites actively and selectively catalyze the formation of relevant prebiotic molecules from formamide in aqueous media. Specific catalytic behaviours are observed, depending on the origin and composition of the chondrites and on the type of water present in the system (activity: thermal > seawater > pure). We report the one-pot synthesis of all the natural nucleobases, of aminoacids and of eight carboxylic acids (forming, from pyruvic acid to citric acid, a continuous series encompassing a large part of the extant Krebs cycle)...
December 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27940338/the-effect-of-alpha-ketoglutaric-acid-on-tyrosinase-activity-and-conformation-kinetics-and-molecular-dynamics-simulation-study
#18
Lin Gou, Jinhyuk Lee, Jun-Mo Yang, Yong-Doo Park, Hai-Meng Zhou, Yi Zhan, Zhi-Rong Lü
Alpha-ketoglutaric acid (AKG) is naturally found in organisms and is a well-known intermediate in the production of ATP or GTP in the Krebs cycle. We elucidated the effects of AKG on tyrosinase activity and conformation via methods of inhibition kinetics integrated with molecular dynamics (MD) simulations. AKG was found to be a reversible inhibitor of tyrosinase (IC50=15±0.5mM) and induced parabolic slope mixed-type inhibition. Based on our newly established equation, the dissociation constant (Kislope) was determined to be 7...
December 7, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/27931520/translational-potential-of-long-term-decreases-in-mitochondrial-lipids-in-a-mouse-model-of-gulf-war-illness
#19
Laila Abdullah, James E Evans, Utsav Joshi, Gogce Crynen, Jon Reed, Benoit Mouzon, Stephan Baumann, Hannah Montague, Zuchra Zakirova, Tanja Emmerich, Corbin Bachmeier, Nancy Klimas, Kimberly Sullivan, Michael Mullan, Ghania Ait-Ghezala, Fiona Crawford
Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10days to GW agents (pyridostigmine bromide and permethrin)...
November 30, 2016: Toxicology
https://www.readbyqxmd.com/read/27924409/antioxidants-reverse-the-changes-in-energy-metabolism-of-rat-brain-after-chronic-administration-of-l-tyrosine
#20
Brena P Teodorak, Giselli Scaini, Milena Carvalho-Silva, Lara M Gomes, Letícia J Teixeira, Joyce Rebelo, Samira D T De Prá, Neila Zeni, Patrícia F Schuck, Gustavo C Ferreira, Emilio L Streck
Tyrosinemia type II is a rare autosomal recessive disease caused by deficiency of hepatic tyrosine aminotransferase and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that high concentrations of tyrosine provoke mitochondrial dysfunction and oxidative stress, in the present study we investigated the in vivo influence of antioxidants (N-acetylcysteine, NAC; and deferoxamine, DFX) administration on the inhibitory effects on parameters of energy metabolism in cerebral cortex, hippocampus and striatum of rats, provoked by chronic administration of L...
December 6, 2016: Metabolic Brain Disease
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