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pyruvate kinase deficiency

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https://www.readbyqxmd.com/read/30091852/phase-1-single-and-multiple-ascending-dose-randomized-studies-of-the-safety-pharmacokinetics-and-pharmacodynamics-of-ag-348-a-first-in-class-allosteric-activator-of-pyruvate-kinase-r-in-healthy-volunteers
#1
Hua Yang, Elizabeth Merica, Yue Chen, Marvin Cohen, Ronald Goldwater, Penelope A Kosinski, Charles Kung, Zheng Jason Yuan, Lee Silverman, Meredith Goldwasser, Bruce A Silver, Sam Agresta, Ann J Barbier
Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials...
August 9, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/30076962/glucose-free-high-protein-diet-improves-hepatomegaly-and-exercise-intolerance-in-glycogen-storage-disease-type-iii-mice
#2
Serena Pagliarani, Sabrina Lucchiari, Gianna Ulzi, Michela Ripolone, Raffaella Violano, Francesco Fortunato, Andreina Bordoni, Stefania Corti, Maurizio Moggio, Nereo Bresolin, Giacomo P Comi
Glycogen disease type III (GSDIII), a rare incurable autosomal recessive disorder due to glycogen debranching enzyme deficiency, presents with liver, heart and skeletal muscle impairment, hepatomegaly and ketotic hypoglycemia. Muscle weakness usually worsens to fixed myopathy and cardiac involvement may present in about half of the patients during disease. Management relies on careful follow-up of symptoms and diet. No common agreement was reached on sugar restriction and treatment in adulthood. We administered two dietary regimens differing in their protein and carbohydrate content, high-protein (HPD) and high-protein/glucose-free (GFD), to our mouse model of GSDIII, starting at one month of age...
August 1, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/30065033/pdk4-deficiency-suppresses-hepatic-glucagon-signaling-by-decreasing-cyclic-amp-levels
#3
Bo-Yoon Park, Jae-Han Jeon, Younghoon Go, Hye Jin Ham, Jeong-Eun Kim, Eun Kyung Yoo, Woong Hee Kwon, Nam-Ho Jeoung, Yong Hyun Jeon, Seung-Hoi Koo, Byung-Gyu Kim, Ling He, Keun-Gyu Park, Robert A Harris, In-Kyu Lee
In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-cAMP response element binding (CREB) signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation which limits the availability of gluconeogenic substrates in the liver. However, in this study up regulation of hepatic PDK4 was found to promote glucagon-mediated expression of gluconeogenic genes whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production...
July 31, 2018: Diabetes
https://www.readbyqxmd.com/read/30028822/a-new-variant-of-pklr-gene-associated-with-mild-hemolysis-may-be-responsible-for-the-misdiagnosis-in-pyruvate-kinase-deficiency
#4
Sultan Aydin Köker, Yeşim Oymak, Paola Bianchi, Salih Gözmen, Tuba H Karapinar, Elisa Fermo, Raziye C Vergin
Pyruvate kinase deficiency (PKD) is the most common glycolytic defect leading to hemolytic anemia. PKD is caused by the mutations in the PKLR gene; however, the detection of a decreased PK activity should be first measured for rapid diagnosis. We report here the case of a 1-year-old girl with mild hemolysis and PKD. At the time of the study, the patient showed a hemoglobin level of 9.5 g/dL, mean corpuscular volume of 93 fL, reticulocyte of 6.7%, and lactate dehydrogenase of 218 IU/L. Peripheral blood smear showed polychromasia, anisocytosis, tear drop cells, fragmented eyrtrocytes, and target cells...
July 19, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/30008376/stabilization-of-the-hypoxia-inducible-transcription-factor-1-alpha-hif-1%C3%AE-in-thiamine-deficiency-is-mediated-by-pyruvate-accumulation
#5
Kristy Zera, Jason Zastre
Vitamin B1, or thiamine is a critical enzyme cofactor required for metabolic function and energy production. Thiamine deficiency (TD) is common in various diseases, and results in severe neurological complications due to diminished mitochondrial function, oxidative stress, excitotoxicity and inflammation. These pathological sequelae result in apoptotic cell death in both neurons and astrocytes in distinct regions, in particular the thalamus and mammillary bodies. Comparable histological injuries in patients with hypoxia/ischemia (H/I) have also been described, suggesting a congruency between the cellular responses to these stresses...
September 15, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29996270/-the-clinical-and-laboratory-characteristics-of-congenital-pyruvate-kinase-deficiency
#6
L Song, Y Li, G X Peng, L Zhang, L P Jing, K Zhou, Y Li, L Ye, J P Li, H H Fan, X Zhao, W R Yang, Y Yang, Y P Zhao, Y Z Xiong, Z J Wu, F K Zhang
Clinical data of 19 patients with congenital pyruvate kinase deficiency were analyzed. Insufficient pyruvate kinase confirmed the diagnosis. Laboratory parameters of hemolysis were summarized. In cases of neonatal hyperbilirubinemia and unexplained hemolytic anemia, pyruvate kinase activity and next generation sequencing test may help the early diagnosis.
July 1, 2018: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
https://www.readbyqxmd.com/read/29991588/htra-of-borrelia-burgdorferi-leads-to-decreased-swarm-motility-and-decreased-production-of-pyruvate
#7
James L Coleman, Alvaro Toledo, Jorge L Benach
Borrelia burgdorferi HtrA (HtrABb) is a serine protease that targets damaged or improperly folded proteins. In our previous studies, HtrABb specifically degraded basic membrane protein BmpD, chemotaxis phosphatase CheX, and outer membrane protein P66. In addition, HtrABb degrades virulence factor BB0323 and components of the extracellular matrix fibronectin and aggrecan. A proteomics-based analysis (two-dimensional difference gel electrophoresis [2-D DIGE], liquid chromatography-mass spectrometry [LC-MS]) of an HtrABb-overexpressing strain of B...
July 10, 2018: MBio
https://www.readbyqxmd.com/read/29935049/the-burden-of-disease-in-pyruvate-kinase-deficiency-patients-perception-of-the-impact-on-health-related-quality-of-life
#8
Rachael F Grace, Jennifer Cohen, Shayna Egan, Ted Wells, Brooke Witherspoon, Aisling Ryan, Sam S Salek, Susan Bodie, Robert J Klaassen
OBJECTIVES: This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). METHODS: Interviews with twenty-one adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods...
June 23, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29913407/the-effect-of-dichloroacetate-in-mouse-models-of-epilepsy
#9
Dylan Durie, Tanya S McDonald, Karin Borges
A recent report has found that glucose oxidation and the activity of pyruvate dehydrogenase (PDH) are reduced in the chronic stage of the pilocarpine mouse epilepsy model. This is likely caused by increased phosphorylation by PDH kinase of the E1α subunit of PDH, downregulating its activity. Inhibition of this phosphorylation has not yet been explored as a possible approach to treat epilepsy. Chronic dichloroacetate (DCA, 50 and 100 mg/kg/day) treatment was tested in acute seizure and the chronic pilocarpine models...
September 2018: Epilepsy Research
https://www.readbyqxmd.com/read/29803284/red-blood-cell-enzyme-disorders
#10
REVIEW
Rachael F Grace, Bertil Glader
Mature red blood cells are reliant on the glycolytic pathway for energy production and the hexose monophosphate shunt for cell protection from oxidative insults. The most common red blood cell enzyme disorders are characterized by hemolysis but with wide clinical variability. Glucose-6-phosphate dehydrogenase deficiency is the most common red cell enzyme disorder worldwide. Frequent clinical presentations include neonatal jaundice and episodic hemolysis after exposure to oxidative stress. Symptoms of pyruvate kinase deficiency and other glycolytic enzyme disorders include neonatal jaundice, chronic hemolytic anemia, gallstones, and transfusion-related and transfusion-independent iron overload...
June 2018: Pediatric Clinics of North America
https://www.readbyqxmd.com/read/29786897/targeted-next-generation-sequencing-for-the-diagnosis-of-patients-with-rare-congenital-anemias
#11
Noa Shefer Averbuch, Orna Steinberg-Shemer, Orly Dgany, Tanya Krasnov, Sharon Noy-Lotan, Joanne Yacobovich, Amir A Kuperman, Antonis Kattamis, Ayelet Ben Barak, Batia Roth-Jelinek, Evgeni Chubar, Evelyn Shabad, Gustavo Dufort, Martin Ellis, Ofir Wolach, Idit Pazgal, Abed Abu Quider, Hagit Miskin, Hannah Tamary
BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing...
May 22, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29755372/use-of-laser-assisted-optical-rotational-cell-analyzer-lorrca-maxsis-in-the-diagnosis-of-rbc-membrane-disorders-enzyme-defects-and-congenital-dyserythropoietic-anemias-a-monocentric-study-on-202-patients
#12
Anna Zaninoni, Elisa Fermo, Cristina Vercellati, Dario Consonni, Anna P Marcello, Alberto Zanella, Agostino Cortelezzi, Wilma Barcellini, Paola Bianchi
Chronic hemolytic anemias are a group of heterogeneous diseases mainly due to abnormalities of red cell (RBC) membrane and metabolism. The more common RBC membrane disorders, classified on the basis of blood smear morphology, are hereditary spherocytosis (HS), elliptocytosis, and hereditary stomatocytoses (HSt). Among RBC enzymopathies, the most frequent is pyruvate kinase (PK) deficiency, followed by glucose-6-phosphate isomerase, pyrimidine 5' nucleotidase P5'N, and other rare enzymes defects. Because of the rarity and heterogeneity of these diseases, diagnosis may be often challenging despite the availability of a variety of laboratory tests...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29732501/pkm2-dependent-metabolic-reprogramming-in-cd4-t-cells-is-crucial-for-hyperhomocysteinemia-accelerated-atherosclerosis
#13
Silin Lü, Jiacheng Deng, Huiying Liu, Bo Liu, Juan Yang, Yutong Miao, Jing Li, Nan Wang, Changtao Jiang, Qingbo Xu, Xian Wang, Juan Feng
Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE-/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling...
June 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29728053/changes-in-nitrogen-availability-lead-to-a-reprogramming-of-pyruvate-metabolism
#14
Nazeer Fataftah, Christina Mohr, Mohammad-Reza Hajirezaei, Nicolaus von Wirén, Klaus Humbeck
BACKGROUND: Low availability of nitrogen (N) severely affects plant growth at different levels, which can be reverted by the resupply of N. To unravel the critical steps in primary metabolism underlying the growth adjustment in response to changes in N availability, transcriptomic and comprehensive metabolite analyses were performed in barley using primary leaves at early and later stages of N deprivation, and after N resupply to N-deficient plants. RESULT: N deficiency in leaves caused differential regulation of 1947 genes, mostly belonging to the functional classes photosynthesis, cell wall degradation, lipid degradation, amino acid degradation, transcription factors, phytohormone metabolism and receptor-like kinases...
May 4, 2018: BMC Plant Biology
https://www.readbyqxmd.com/read/29610156/successful-liver-transplants-for-liver-failure-associated-with-pyruvate-kinase-deficiency
#15
Marie-Eve Chartier, Lara Hart, Massimiliano Paganelli, Najma Ahmed, Marc Bilodeau, Fernando Alvarez
Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic hemolytic anemia, and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and splenomegaly. Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal cholestasis and a young adult with a severe form of PKD and having been transfusion dependent during childhood...
April 2018: Pediatrics
https://www.readbyqxmd.com/read/29603325/loss-of-pdk4-switches-the-hepatic-nf-%C3%AE%C2%BAb-tnf-pathway-from-pro-survival-to-pro-apoptosis
#16
Jianguo Wu, Yulan Zhao, Young-Ki Park, Ji-Young Lee, Ling Gao, Jiajun Zhao, Li Wang
It has been established that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF-κB is required for tumor necrosis factor (TNF)-induced hepatocyte apoptosis. In this study, we demonstrate that this pro-survival pathway is switched to pro-apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)-deficient conditions. PDK4-deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c-Jun N-terminal Kinase (JNK) activation, and reduction of glutathione (GSH)...
March 30, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29556780/taurine-supplementation-induces-long-term-beneficial-effects-on-glucose-homeostasis-in-ob-ob-mice
#17
Patricia Cristine Borck, Jean Franciesco Vettorazzi, Renato Chaves Souto Branco, Thiago Martins Batista, Junia Carolina Santos-Silva, Vanessa Yumi Nakanishi, Antonio Carlos Boschero, Rosane Aparecida Ribeiro, Everardo Magalhães Carneiro
The sulfur-containing amino acid, taurine (Tau), regulates glucose and lipid homeostasis under normal, pre- and diabetic conditions. Here, we aimed to verify whether Tau supplementation exerts its beneficial effects against obesity, hyperglycemia and alterations in islet functions, in leptin-deficient obese (ob/ob), over a long period of treatment. From weaning until 12 months of age, female ob/ob mice received, or not, 5% Tau in drinking water (obTau group). After this period, a reduction in hypertriglyceridemia and an improvement in glucose tolerance and insulin sensitivity were observed in obTau mice...
June 2018: Amino Acids
https://www.readbyqxmd.com/read/29549173/clinical-spectrum-of-pyruvate-kinase-deficiency-data-from-the-pyruvate-kinase-deficiency-natural-history-study
#18
Rachael F Grace, Paola Bianchi, Eduard J van Beers, Stefan W Eber, Bertil Glader, Hassan M Yaish, Jenny M Despotovic, Jennifer A Rothman, Mukta Sharma, Melissa M McNaull, Elisa Fermo, Kimberly Lezon-Geyda, D Holmes Morton, Ellis J Neufeld, Satheesh Chonat, Nina Kollmar, Christine M Knoll, Kevin Kuo, Janet L Kwiatkowski, Dagmar Pospíšilová, Yves D Pastore, Alexis A Thompson, Peter E Newburger, Yaddanapudi Ravindranath, Winfred C Wang, Marcin W Wlodarski, Heng Wang, Susanne Holzhauer, Vicky R Breakey, Joachim Kunz, Sujit Sheth, Melissa J Rose, Heather A Bradeen, Nolan Neu, Dongjing Guo, Hasan Al-Sayegh, Wendy B London, Patrick G Gallagher, Alberto Zanella, Wilma Barcellini
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity...
May 17, 2018: Blood
https://www.readbyqxmd.com/read/29545180/hepatic-glucose-6-phosphatase-%C3%AE-deficiency-leads-to-metabolic-reprogramming-in-glycogen-storage-disease-type-ia
#19
Jun-Ho Cho, Goo-Young Kim, Brian C Mansfield, Janice Y Chou
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis...
April 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29519373/novel-mutations-associated-with-pyruvate-kinase-deficiency-in-brazil
#20
Maria Carolina Costa Melo Svidnicki, Andrey Santos, Jhonathan Angel Araujo Fernandez, Ana Paula Hitomi Yokoyama, Isis Quezado Magalhães, Vitoria Regia Pereira Pinheiro, Silvia Regina Brandalise, Paulo Augusto Achucarro Silveira, Fernando Ferreira Costa, Sara Teresinha Olalla Saad
BACKGROUND: Pyruvate kinase deficiency is a hereditary disease that affects the glycolytic pathway of the red blood cell, causing nonspherocytic hemolytic anemia. The disease is transmitted as an autosomal recessive trait and shows a marked variability in clinical expression. This study reports on the molecular characterization of ten Brazilian pyruvate kinase-deficient patients and the genotype-phenotype correlations. METHOD: Sanger sequencing and in silico analysis were carried out to identify and characterize the genetic mutations...
January 2018: Revista Brasileira de Hematologia e Hemoterapia
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