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https://www.readbyqxmd.com/read/28928232/sdhd-ablation-promotes-thyroid-tumorigenesis-by-inducing-a-stem-like-phenotype
#1
Amruta Ashtekar, Danielle Huk, Alexa Magner, Krista La Perle, Xiaoli Zhang, Jose Piruat, Jose Lopez-Barneo, Sissy Jhiang, Lawrence Kirschner
Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas, and pheochromocytomas. In recent studies, missense mutations in the Succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (SDHD) in the thyroid...
September 19, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28920462/involvement-of-atrial-natriuretic-peptide-in-abrogated-cardioprotective-effect-of-ischemic-preconditioning-in-ovariectomized-rat-heart
#2
V K Vishwakarma, A Goyal, J K Gupta, P K Upadhyay, H N Yadav
BACKGROUND: Nitric oxide (NO) is an effective mediator of ischemic preconditioning (IPC)-induced cardioprotection. Atrial natriuretic peptide (ANP) is downregulated after ovariectomy, which results in reduction in the level of NO. The present study deals with the investigation of the role of ANP in abrogated cardioprotective effect of IPC in the ovariectomized rat heart. METHODS: Heart was isolated from ovariectomized rat and mounted on Langendorff's apparatus, subjected to 30 min of ischemia and 120 min of reperfusion...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/28916726/the-nqo1-bioactivatable-drug-%C3%AE-lapachone-alters-the-redox-state-of-nqo1-pancreatic-cancer-cells-causing-perturbation-in-central-carbon-metabolism
#3
Molly A Silvers, Stanislaw Deja, Naveen Singh, Robert A Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S Beg, Shawn C Burgess, Ralph J DeBerardinis, David A Boothman, Matthew E Merritt
Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide, then peroxide formation, which damages DNA and causes hyperactivation of poly (ADP-ribose) polymerase (PARP), resulting in extensive NAD+/ATP depletion...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28910859/investigation-of-the-effects-of-storage-and-freezing-on-mixes-of-heavy-labeled-metabolite-and-amino-acid-standards
#4
Rachel Culp-Hill, Julie A Reisz, Kirk C Hansen, Angelo D'Alessandro
RATIONALE: High-throughput metabolomics has now made it possible for small/medium-sized laboratories to analyze thousands of samples/year from the most diverse biological matrices including biofluids, cell and tissue extracts. In large scale metabolomics studies, stable isotope-labeled standards are increasingly used to normalize for matrix effects and control for technical reproducibility (e.g. extraction efficiency, chromatographic retention times and mass spectrometry signal stability)...
September 14, 2017: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/28874678/mitochondrial-cyclophilin-d-ablation-is-associated-with-the-activation-of-akt-p70s6k-pathway-in-the-mouse-kidney
#5
Jelena Klawitter, Alexander Pennington, Jost Klawitter, Joshua M Thurman, Uwe Christians
The mitochondrial matrix protein cyclophilin D (CypD) is an essential component of the mitochondrial permeability transition pore (MPTP). Here we characterized the effects of CypD ablation on bioenergetics in the kidney. CypD loss triggers a metabolic shift in Ppif-/- male and female mouse kidneys towards glycolysis and Krebs cycle activity. The shift is accompanied by increased glucose consumption and a transcriptional upregulation of effectors of glucose metabolism in the kidney. These included activation of Akt, AMPK (only in males) and p70S6K kinases...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28857669/evaluation-of-extraction-methods-for-the-identification-of-proteins-from-date-palm-phoenix-dactylifera-l-seed-and-flesh
#6
Hooi Xian Lee, Fisal Ahmad, Bahruddin Saad, Mohd Nazri Ismail
Date fruits are well known to be very nutritious. Nevertheless, the protein content of the fruit, particularly the seed and flesh is still understudied, largely due to their difficult physical characteristics. This study was conducted to compare three different protein extraction methods which were the TCA-acetone (TCA-A), phenol (Phe), and TCA-acetone-phenol (TCA-A-Phe), and to perform proteomic analysis on date palm seed and flesh. Phe extraction method showed the highest protein yields for both seed (8.26 mg/ g) and flesh (1...
August 31, 2017: Preparative Biochemistry & Biotechnology
https://www.readbyqxmd.com/read/28846566/activation-of-pyruvate-dehydrogenase-activity-bydichloroacetate-improves-survival-and-neurologic-outcomes-after-cardiac-arrest-in-rats
#7
Peng Wang, Mingdi Chen, Zhengfei Yang, Tao Yu, Jie Zhu, Lili Zhou, Jiali Lin, Xiangshao Fang, Zitong Huang, Longyuan Jiang, Wanchun Tang
No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which activates pyruvate dehydrogenase (PDH), and increases cell adenosine triphosphate (ATP) production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in an asphyxial cardiac arrest rat model. Asphyxial cardiac arrest was established by endotracheal tube clamping...
August 25, 2017: Shock
https://www.readbyqxmd.com/read/28842639/metabolomic-analysis-reveals-vitamin-d-induced-decrease-in-polyol-pathway-and-subtle-modulation-of-glycolysis-in-hek293t-cells
#8
G C Santos, J D Zeidler, J A Pérez-Valencia, A C B Sant'Anna-Silva, A T Da Poian, T El-Bacha, F C L Almeida
We combined (1)H NMR metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations. Activation of the polyol pathway, was the most important consequence of cell exposure to high glucose concentration, resembling cells exposed to hyperglycemia. Vitamin D induced alterations in HEK293T cells metabolism, including a decrease in sorbitol, glycine, glutamate, guanine. Vitamin D modulated glycolysis by increasing phosphoglycerate mutase and decreasing enolase activities, changing carbon fate without changing glucose consumption, lactate export and Krebs cycle...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28838288/overexpression-of-drosophila-frataxin-triggers-cell-death-in-an-iron-dependent-manner
#9
Oliver Edenharter, Janik Clement, Stephan Schneuwly, Juan A Navarro
Friedreich ataxia (FRDA) is the most important autosomal recessive ataxia in the Caucasian population. FRDA patients display severe neurological and cardiac symptoms that reflect a strong cellular and axonal degeneration. FRDA is caused by a loss of function of the mitochondrial protein frataxin which impairs the biosynthesis of iron-sulfur clusters and in turn the catalytic activity of several enzymes in the Krebs cycle and the respiratory chain leading to a diminished energy production. Although FRDA is due to frataxin depletion, overexpression might also be very helpful to better understand cellular functions of frataxin...
August 24, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28828968/biomedical-application-of-polymers-a-case-study-of-non-cns-drugs-becoming-cns-acting-drugs
#10
Saganuwan Alhaji Saganuwan
The transport of CNS acting drugs across blood-brain barrier is complex and guided by the molecular weight, PH, physicochemical and pathological state of the BBB among others. In view of this, literatures were assessed for possible conversion of Non-CNS to CNS acting drugs, whose ability to penetrate CNS can be improved using polymers for biomedical applications. The findings have shown that compounds with pyridine, pyrrole, carboxamide, pyridone among others can be converted to CNS acting drugs that can be loaded in specialized carrier polymers for transportation across BBB...
August 20, 2017: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28819434/identification-of-transcription-factor-yy1-as-a-regulator-of-a-prostate-cancer-specific-pathway-using-proteomic-analysis
#11
Arum Park, Jiyeong Lee, Sora Mun, Doo Jin Kim, Byung Heun Cha, Kyong Tae Moon, Tag Keun Yoo, Hee-Gyoo Kang
Prostate-specific antigen, a biomarker used to diagnose prostate cancer, exhibits poor sensitivity. Although previous studies have focused on identifying a new diagnostic biomarker, the molecules or networks identified in these studies are also present in other cancers, making it difficult to detect prostate cancer specifically. A unique characteristic of the prostate gland is the increased mitochondrial energy metabolism when normal prostate cells progress to cancer cells. Thus, we attempted to find a prostate cancer-specific signature present in this unique environment...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28814730/quantification-of-lactate-from-various-metabolic-pathways-and-quantification-issues-of-lactate-isotopologues-and-isotopmers
#12
Wei Zhang, Cheng Guo, Kezhi Jiang, Minfeng Ying, Xun Hu
(13)C-labeled glucose combined with chromatography and mass spectrometry enables us to decipher the percentage of lactate generated from various metabolic pathways. We showed that lactate derived from glycolysis, pentose phosphate pathway, Krebs cycle, and other sources accounted for 82-90%, 6.0-11%, 0.67-1.8% and 1.5-7.9%, respectively, depending on different types of cells. When using glucose isotopomers ([1-(13)C]-, [3-(13)C]-, [4-(13)C]-, and [6-(13)C]glucose) or isotopologues ([1,2-(13)C2]- and [1,2,3-(13)C3]glucose) for tracing, the ratio of lactate derived from glucose carbon 1, 2, 3 over 4, 5, 6 via glycolysis varied significantly, ranging from 1...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28812671/sulfate-radicals-enable-a-non-enzymatic-krebs-cycle-precursor
#13
Markus A Keller, Domen Kampjut, Stuart A Harrison, Markus Ralser
The evolutionary origins of the Krebs cycle (tricarboxylic acid cycle) are not currently clear. Despite the existence of a simple non-enzymatic Krebs cycle catalyst being dismissed only a few years ago as 'an appeal to magic', citrate and other intermediates have since been discovered on a carbonaceous meteorite and do interconvert non-enzymatically. To identify a metabolism-like non-enzymatic Krebs cycle catalyst, we used combinatorial, quantitative high-throughput metabolomics to systematically screen iron and sulfate compounds in a reaction mixture that orients on the typical components of Archaean sediment...
March 13, 2017: Nature ecology & evolution
https://www.readbyqxmd.com/read/28771732/direct-assessment-of-the-metabolic-origin-of-carbon-atoms-in-glutamate-from-illuminated-leaves-using-13-c-nmr
#14
Cyril Abadie, Jérémy Lothier, Edouard Boex-Fontvieille, Adam Carroll, Guillaume Tcherkez
Glutamate (Glu) is the cornerstone of nitrogen assimilation and photorespiration in illuminated leaves. Despite this crucial role, our knowledge of the flux to Glu de novo synthesis is rather limited. Here, we used isotopic labelling with (13) CO2 and (13) C-NMR analyses to examine the labelling pattern and the appearance of multi-labelled species of Glu molecules to trace the origin of C-atoms found in Glu. We also compared this with (13) C-labelling patterns in Ala and Asp, which reflect citrate (and thus Glu) precursors, that is, pyruvate and oxaloacetate...
August 3, 2017: New Phytologist
https://www.readbyqxmd.com/read/28762682/-use-of-citrate-in-patients-with-nephrolithiasis
#15
REVIEW
Martino Marangella
Citrate is a tricarboxylic acid and an intermediate metabolite of Krebs cycle. It contributes to oxidative metabolism of both kidney and liver. Alkaline sodium or potassium salts have the potential to increase alkaline reserve. In the kidney citrate is completely filtered at the glomerulus, undergoing to 10-40% tubular resorption. Renal insufficiency, even early, metabolic acidosis, potassium depletion induce hypocitraturia. Its importance in nephrolithiasis stems from its ability to form soluble complexes with calcium and to interfere with crystal formation, thus exerting a dual inhibition, thermodynamic and kinetic...
August 1, 2017: Giornale Italiano di Nefrologia: Organo Ufficiale Della Società Italiana di Nefrologia
https://www.readbyqxmd.com/read/28758940/non-targeted-metabolomics-analysis-of-golden-retriever-muscular-dystrophy-affected-muscles-reveals-alterations-in-arginine-and-proline-metabolism-and-elevations-in-glutamic-and-oleic-acid-in-vivo
#16
Muhammad Abdullah, Joe N Kornegay, Aubree Honcoop, Traci L Parry, Cynthia J Balog-Alvarez, Sara K O'Neal, James R Bain, Michael J Muehlbauer, Christopher B Newgard, Cam Patterson, Monte S Willis
BACKGROUND: Like Duchenne muscular dystrophy (DMD), the Golden Retriever Muscular Dystrophy (GRMD) dog model of DMD is characterized by muscle necrosis, progressive paralysis, and pseudohypertrophy in specific skeletal muscles. This severe GRMD phenotype includes moderate atrophy of the biceps femoris (BF) as compared to unaffected normal dogs, while the long digital extensor (LDE), which functions to flex the tibiotarsal joint and serves as a digital extensor, undergoes the most pronounced atrophy...
July 29, 2017: Metabolites
https://www.readbyqxmd.com/read/28744858/d-malate-decreases-renal-content-of-%C3%AE-ketoglutarate-a-driving-force-of-organic-anion-transporters-oat1-and-oat3-resulting-in-inhibited-tubular-secretion-of-phenolsulfonphthalein-in-rats
#17
Yuichi Uwai, Tatsuya Kawasaki, Tomohiro Nabekura
D-Malate inhibits a Krebs cycle enzyme and the tubular transport of α-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. In this study, we examined effects of D-malate on the rat organic anion transport system. Uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by D-malate and L-malate. Until 60 min after the intravenous injection of phenolsulfonphthalein (PSP), a typical substrate of the renal organic anion transporters, as a bolus to rats, 47...
July 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28720665/targeted-exome-sequencing-of-krebs-cycle-genes-reveals-candidate-cancer-predisposing-mutations-in-pheochromocytomas-and-paragangliomas
#18
Laura Remacha, Iñaki Comino-Méndez, Susan Richter, Laura Contreras, Maria Currás-Freixes, Guillermo Pita, Rocío Letón, Antonio Galarreta, Rafael Torres-Pérez, Emiliano Honrado, Scherezade Jiménez, Lorena Maestre, Sebastian Moran, Manel Esteller, Jorgina Satrústegui, Graeme Eisenhofer, Mercedes Robledo, Alberto Cascon
Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes. <p>Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes...
July 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28712602/anaplerotic-therapy-in-propionic-acidemia
#19
Nicola Longo, Leisa B Price, Eduard Gappmaier, Nancy L Cantor, Sharon L Ernst, Carrie Bailey, Marzia Pasquali
BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7...
September 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28710072/circulating-acylcarnitine-profile-in-human-heart-failure-a-surrogate-of-fatty-acid-metabolic-dysregulation-in-mitochondria-and-beyond
#20
Matthieu Ruiz, Francois Labarthe, Annik Fortier, Bertrand Bouchard, Julie Thompson Legault, Virginie Bolduc, Odile Rigal, Jane Chen, Anique Ducharme, Peter A Crawford, Jean-Claude Tardif, Christine Des Rosiers
Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FA), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction, display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 controls and 68 HF patients, exhibiting depressed left ventricular ejection fraction (25...
July 14, 2017: American Journal of Physiology. Heart and Circulatory Physiology
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