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pyruvate kinase deficiency

J Key, A K Mueller, S Gispert, L Matschke, I Wittig, O Corti, C Münch, N Decher, G Auburger
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase...
February 11, 2019: Neurobiology of Disease
Rachael F Grace, D Mark Layton, Wilma Barcellini
Novel therapies in development have brought a new focus on pyruvate kinase deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy...
January 25, 2019: British Journal of Haematology
Helen E Collins, Betty M Pat, Luyun Zou, Silvio H Litovsky, Adam Raymond Wende, Martin E Young, John C Chatham
The ER/SR Ca2+ sensor, stromal interaction molecule 1 (STIM1), a key mediator of store-operated calcium entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (cr STIM1-KO) results in age-dependent ER stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-week old cr STIM1-KO mice exhibited a significant reduction in both oxidative and non-oxidative glucose utilization...
December 21, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Poonam Tripathi, Ravindra Kumar, Sarita Agarwal
Thalassemia and other hemoglobinopathies together with red cell enzymopathies are a common cause of anemia, which can be prevented by population screening and genetic counseling. This study was designed to screen the anemic patients for thalassemia, structural hemoglobin variants and red cell enzymopathies. A total of 17047 cases were evaluated from 2009 to 2018 for thalassemia, hemoglobin variants, glucose 6 phosphate dehydrogenase deficiency, pyruvate kinase deficiency and hereditary spherocytosis. Patients' records were entered in a Microsoft excel sheet and a spectrum of disorders was evaluated...
November 2018: Intractable & Rare Diseases Research
Themis Thoudam, Chae-Myeong Ha, Jaechan Leem, Dipanjan Chanda, Jong-Seok Park, Hyo-Jeong Kim, Jae-Han Jeon, Yeon-Kyung Choi, Suthat Liangpunsakul, Yang Hoon Huh, Tae-Hwan Kwon, Keun-Gyu Park, Robert A Harris, Kyu-Sang Park, Hyun-Woo Rhee, In-Kyu Lee
Mitochondria-associated ER membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4) interacts with and stabilizes IP3R1-GRP75-VDAC1 complex at the MAM interface...
December 6, 2018: Diabetes
M S Salek, T Ionova, J R Johns, E N Oliva
PURPOSE: Pyruvate kinase deficiency (PKD) is a rare disease and understanding of its epidemiology and associated burden remains limited. With no current curative therapy, clinical manifestations can be life threatening, clinically managed by maintaining adequate hemoglobin levels through transfusion and subsequent support, but with frequent complications. Treatment goals are to maintain/improve the patient's quality of life. With new therapies, reliable, valid, and relevant patient-reported outcome (PRO) tools are required for use in clinical trials...
November 19, 2018: Quality of Life Research
Xinxing Ouyang, Yuheng Han, Guojun Qu, Man Li, Omotooke Arojo, Hongxiang Sun, Xiaobo Liu, Dou Liu, Lei Chen, Qiang Zou, Bing Su
Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4-CD8- double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis...
November 14, 2018: Journal of Molecular Cell Biology
Paola Bianchi, Elisa Fermo, Bertil Glader, Hitoshi Kanno, Archana Agarwal, Wilma Barcellini, Stefan Eber, James D Hoyer, David J Kuter, Tabita Magalhães Maia, Maria Del Mar Mañu-Pereira, Theodosia A Kalfa, Serge Pissard, José-Carlos Segovia, Eduard van Beers, Patrick G Gallagher, David C Rees, Richard van Wijk
Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines...
October 25, 2018: American Journal of Hematology
Guillaume Vignon, Roxane Jeanneau, Julien Labrousse, Sébastien Aubrit, Philippe Mottaz, François Carrère, Pierre-Frédéric Augereau, Philippe Aucher, Franck Lellouche
The most frequent causes of hemolytic anemias are immune or infectious diseases, drug induced hemolysis, thrombotic microangiopathies, hereditary spherocytosis, glucose-6-phosphate dehydrogenase or pyruvate kinase deficiencies, thalassemia's and sickle cell disease. Sometimes no cause is found because a rarer etiology is involved. The goal of this review is to remember some unfrequent constitutional or acquired causes and to point out difficulties to avoid wrong interpretations of analysis results.
October 1, 2018: Annales de Biologie Clinique
Eduard J van Beers, Stephanie van Straaten, D Holmes Morton, Wilma Barcellini, Stefan W Eber, Bertil Glader, Hassan M Yaish, Satheesh Chonat, Janet L Kwiatkowski, Jennifer A Rothman, Mukta Sharma, Ellis J Neufeld, Sujit Sheth, Jenny M Despotovic, Nina Kollmar, Dagmar Pospisilova, Christine M Knoll, Kevin Kuo, Yves D Pastore, Alexis A Thompson, Peter E Newburger, Yaddanapudi Ravindranath, Winfred C Wang, Marcin W Wlodarski, Heng Wang, Susanne Holzhauer, Vicky R Breakey, Madeleine Verhovsek, Joachim Kunz, Melissa A McNaull, Melissa J Rose, Heather A Bradeen, Kathryn Addonizio, Anran Li, Hasan Al-Sayegh, Wendy B London, Rachael F Grace
No abstract text is available yet for this article.
September 13, 2018: Haematologica
Victor Bobée, Sylvie Daliphard, Aurélien Schrapp, Agnès Lahary
INTRODUCTION: Development of additional parameters for complete blood count has emerged in recent hematology analyzers, leading to many publications. However, few studies have been conducted on advanced RBC parameters and hemolytic anemias. We investigated the interest of Sysmex unique parameters, MicroR and HypoHe, as well as the immature fraction of reticulocytes (IRF) in combination with complete blood and reticulocyte count, for screening hereditary spherocytosis (HS) and pyruvate kinase deficiency...
September 5, 2018: International Journal of Laboratory Hematology
Vedad Delic, Kenyaria Noble, Sandra Zivkovic, Tam-Anh Phan, Christian Reynes, Yumeng Zhang, Oluwakemi Phillips, Charles Claybaker, Yen Ta, Vinh B Dinh, Josean Cruz, Tomas A Prolla, Patrick C Bradshaw
Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and wild-type (WT) mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate-containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species (ROS) production under standard conditions...
November 16, 2018: Biology Open
Shubha Ghosh Dastidar, Ganapathy Jagatheesan, Petra Haberzettl, Jasmit Shah, Bradford G Hill, Aruni Bhatnagar, Daniel J Conklin
Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, non-alcoholic fatty liver disease (NAFLD) and diabetes. The multifunctional GST Pi isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet (HFD) in wild type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver...
August 28, 2018: American Journal of Physiology. Endocrinology and Metabolism
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
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...
October 2018: Biochimica et biophysica acta. Molecular basis of disease
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)-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, this study found upregulation of hepatic PDK4 promoted 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...
October 2018: Diabetes
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
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
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]
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
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