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Pyruvate dehydrogenase

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https://www.readbyqxmd.com/read/28918066/enzymatic-testing-sensitivity-variability-and-practical-diagnostic-algorithm-for-pyruvate-dehydrogenase-complex-pdc-deficiency
#1
Ha Kyung Shin, George Grahame, Shawn E McCandless, Douglas S Kerr, Jirair K Bedoyan
Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder...
September 8, 2017: Molecular Genetics and Metabolism
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
#2
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/28915065/targeting-hif-1%C3%AE-pdk1-axis-by-dichloroacetate-dca-suppresses-bleomycin-induced-pulmonary-fibrosis
#3
Justin Goodwin, Hyunsung Choi, Meng-Hsiung Hsieh, Michael L Neugent, Jung-Mo Ahn, Heather N Hayenga, Pankaj K Singh, David B Shackelford, In-Kyu Lee, Vladimir Shulaev, Shanta Dhar, Norihiko Takeda, Jung-Whan Kim
RATIONALE: Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences such as hypoxia contribute to their sustained activation and differentiation is poorly understood. OBJECTIVES: As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the pre-clinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis...
September 15, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28914437/salutary-potential-of-ethanolic-extract-of-avocado-fruit-on-anomalous-carbohydrate-metabolic-key-enzymes-in-hepatic-and-renal-tissues-of-hyperglycaemic-albino-rats
#4
U S Mahadeva Rao
OBJECTIVE: To assess the beneficial potential of ethanolic extract of avocado fruit on abnormal carbohydrate metabolic key enzymes in hepatic and renal tissues in streptozotocin (STZ) induced hyperglycemic albino rats. METHODS: Twenty-four male albino rats were randomly divided into four groups with six in each group by simple random sampling method. Group 1 as control rats; Group 2 as STZ induced diabetic rats; Group 3 as diabetic rats treated with avocado fruit extract (AFE), 300 mg/kg as aqueous suspension orally for 30 days; Group 4 as diabetic rats treated with gliclazide (5 mg/kg) in aqueous solution orally for 30 days...
September 15, 2017: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28913435/iba57-mutations-abrogate-iron-sulfur-cluster-assembly-leading-to-cavitating-leukoencephalopathy
#5
Akihiko Ishiyama, Chika Sakai, Yuichi Matsushima, Satoru Noguchi, Satomi Mitsuhashi, Yukari Endo, Yukiko K Hayashi, Yoshiaki Saito, Eiji Nakagawa, Hirofumi Komaki, Kenji Sugai, Masayuki Sasaki, Noriko Sato, Ikuya Nonaka, Yu-Ichi Goto, Ichizo Nishino
OBJECTIVE: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. METHODS: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL...
October 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28904365/rnai-mediated-silencing-of-a-pyruvate-dehydrogenase-kinase-enhances-triacylglycerol-biosynthesis-in-the-oleaginous-marine-alga-nannochloropsis-salina
#6
Xiaonian Ma, Lina Yao, Bo Yang, Yuan Kun Lee, Feng Chen, Jin Liu
Oleaginous microalgae have been emerging as the third-generation feedstocks for biofuel production. Genetic manipulation for improving triacylglycerol (TAG) accumulation represents a promising approach towards the economics of microalgal biofuels. Acetyl-CoA, the essential carbon precursor for de novo fatty acid biosynthesis, can be derived from pyruvate catalyzed by pyruvate dehydrogenase, which is negatively regulated by pyruvate dehydrogenase kinase (PDK). In the present study, we characterized a PDK gene (NsPDK) from Nannochloropsis salina...
September 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900027/sirtuin-lipoamidase-activity-is-conserved-in-bacteria-as-a-regulator-of-metabolic-enzyme-complexes
#7
Elizabeth A Rowland, Todd M Greco, Caroline K Snowden, Anne L McCabe, Thomas J Silhavy, Ileana M Cristea
Lipoic acid is an essential metabolic cofactor added as a posttranslational modification on several multimeric enzyme complexes. These protein complexes, evolutionarily conserved from bacteria to humans, are core regulators of cellular metabolism. While the multistep enzymatic process of adding lipoyl modifications has been well characterized in Escherichia coli, the enzyme required for the removal of these lipoyl moieties (i.e., a lipoamidase or delipoylase) has not yet been identified. Here, we describe our discovery of sirtuins as lipoamidases in bacteria and establish their conserved substrates...
September 12, 2017: MBio
https://www.readbyqxmd.com/read/28899927/mir-138-protects-cardiac-cells-against-hypoxia-through-modulation-of-glucose-metabolism-by-targeting-pyruvate-dehydrogenase-kinase-1-pdk1
#8
Hang Zhu, Hao Xue, Qin-Hua Jin, Jun Guo, Yun-Dai Chen
Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MicroRNAs (miRNAs) are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3'UTR region of their target mRNAs (12). Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions (13-17). Pyruvate Dehydrogenase Kinase 1 (PDK1) is a kinase which phosphorylates Pyruvate Dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration...
September 12, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28893177/integrated-application-of-transcriptomics-and-metabolomics-provides-insights-into-glycogen-content-regulation-in-the-pacific-oyster-crassostrea-gigas
#9
Busu Li, Kai Song, Jie Meng, Li Li, Guofan Zhang
BACKGROUND: The Pacific oyster Crassostrea gigas is an important marine fishery resource, which contains high levels of glycogen that contributes to the flavor and the quality of the oyster. However, little is known about the molecular and chemical mechanisms underlying glycogen content differences in Pacific oysters. Using a homogeneous cultured Pacific oyster family, we explored these regulatory networks at the level of the metabolome and the transcriptome. RESULTS: Oysters with the highest and lowest natural glycogen content were selected for differential transcriptome and metabolome analysis...
September 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28887303/dynamic-nuclear-polarization-facilitates-monitoring-of-pyruvate-metabolism-in-trypanosoma-brucei
#10
You Zhuo, Ciro D Cordeiro, S Khan Hekmatyar, Roberto Docampo, James H Prestegard
Dynamic nuclear polarization (DNP) provides sensitivity improvements that make NMR a viable method for following metabolic conversions in real time. There are now many in vivo applications to animal systems and even to diagnosis of human disease. However, application to microbial systems is rare. Here we demonstrate its application to the pathogenic protozoan, Trypanosoma brucei, using hyperpolarized (13)C1- pyruvate as a substrate and compare the parasite metabolism to that of commonly cultured mammalian cell lines, HEK-293 and Hep-G2...
September 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28886987/consequences-of-the-natural-retinoid-retinoid-x-receptor-ligands-action-in-human-breast-cancer-mda-mb-231-cell-line-focus-on-functional-proteomics
#11
D Flodrova, L Toporova, M Lastovickova, D Macejova, L Hunakova, J Brtko, J Bobalova
The main intention of this study was the investigation of impact of natural biologically active ligands of nuclear retinoid/retinoid X receptors (all-trans and 9-cis retinoic acid) on proteomic pattern in human estrogen receptor negative breast cancer cell line MDA-MB-231. For this purpose, proteomic strategies based on bottom-up method were applied. The total cell proteins were extracted utilizing a commercially Radio-Immunoprecipitation Assay (RIPA) buffer and separated on 2D sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS-PAGE)...
September 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28886081/orexin-a-affects-hepg2-human-hepatocellular-carcinoma-cells-glucose-metabolism-via-hif-1%C3%AE-dependent-and-independent-mechanism
#12
Xing Wan, Yuanyuan Liu, Yuyan Zhao, Xiaoqi Sun, Dongxiao Fan, Lei Guo
Orexins are hypothalamic neuropeptides that regulate feeding, reward, wakefulness and energy homeostasis. The present study sought to characterize the involvement of orexin A in glucose metabolism in HepG2 human hepatocellular carcinoma cells, and investigated the role of hypoxia-inducible factor-1α (HIF-1α) in the response. HepG2 cells were exposed to different concentrations of orexin A (10-9 to 10-7 M) in vitro, without or with the orexin receptor 1 (OX1R) inhibitor (SB334867), HIF-1α inhibitor (YC-1) or a combination of both inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28883002/genetic-dissociation-of-glycolysis-and-the-tca-cycle-affects-neither-normal-nor-neoplastic-proliferation
#13
Laura E Jackson, Sucheta Kulkarni, Huabo Wang, Jie Lu, James M Dolezal, Sivakama S Bharathi, Sarangarajan Ranganathan, Mulchand S Patel, Rahul Deshpande, Frances Alencastro, Stacy G Wendell, Eric S Goetzman, Andrew W Duncan, Edward V Prochownik
Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation...
September 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28881758/suppression-of-pyruvate-dehydrogenase-kinase-2-re-sensitizes-paclitaxel-resistant-human-lung-cancer-cells-to-paclitaxel
#14
Hong Sun, Anyou Zhu, Xiang Zhou, Fengchao Wang
Despite impressive initial clinical responses, the majority of lung cancer patients treated with paclitaxel eventually develop resistance to the drug. Pyruvate dehydrogenase kinase-2 (PDK2) is a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumors. In this study, the role of PDK2 in mediating paclitaxel resistance in lung cancer cells was investigated using biochemical and isotopic tracing methods. Increased expression of PDK2 was observed in paclitaxel-resistant cells ascompared totheir parental cells...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881757/antagonistic-effects-of-selenium-on-cadmium-induced-apoptosis-by-restoring-the-mitochondrial-dynamic-equilibrium-and-energy-metabolism-in-chicken-spleens
#15
Zhe Xu, Xi Jin, Tingru Pan, Tianqi Liu, Na Wan, Shu Li
The aim of this study was to investigate the mechanism of cadmium-induced apoptosis in chicken spleens and the antagonistic effects of selenium. We duplicated the selenium-cadmium interaction model and examined the expression of apoptosis-, immune-, mitochondrial dynamics- and energy metabolism-related genes. The results demonstrated that after treatment with cadmium, the frequency of apoptosis was significantly increased, and the morphological characteristics of apoptosis were observed. The expression of pro-apoptotic genes was increased, and that of anti-apoptotic genes was decreased...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881665/hpv-associated-differential-regulation-of-tumor-metabolism-in-oropharyngeal-head-and-neck-cancer
#16
Young-Suk Jung, Abdo J Najy, Wei Huang, Seema Sethi, Michael Snyder, Wael Sakr, Gregory Dyson, Maik Hüttemann, Icksoo Lee, Rouba Ali-Fehmi, Silvia Franceschi, Linda Struijk, Harold E Kim, Ikuko Kato, Hyeong-Reh Choi Kim
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880546/transcriptomic-and-functional-analyses-on-the-effects-of-dioxin-on-insulin-secretion-of-pancreatic-islets-and-%C3%AE-cells
#17
Keng Po Lai, Hin Ting Wan, Alice Hoi-Man Ng, Jing Woei Li, Ting-Fung Chan, Chris Kong-Chu Wong
In this study, transcriptomic and Ingenuity Pathway Analysis (IPA) underlined that an ex-vivo TCDD treatment (0.1 nM) stimulated insulin-release in mouse pancreatic islets via the effect on the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways. Functional studies using both ex-vivo islets and the mouse β-cell-line (Min-6) validated the stimulatory effects of TCDD (0.1 and 1 nM) on basal-insulin secretion. At 0.1 nM TCDD treatment on Min-6, western blot analysis showed activation of ERK1/2 and decreased expression of pyruvate dehydrogenase kinase (PDK)...
September 7, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28878400/thiamine-antagonists-trigger-p53-dependent-apoptosis-in-differentiated-sh-sy5y-cells
#18
Sergiy Chornyy, Yulia Parkhomenko, Nataliya Chorna
Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiamine homeostasis. Impairment in thiamine metabolism can be induced experimentally via interference with the thiamine uptake and/or inhibition of the thiamin pyrophosphate-dependent enzymes using thiamine antagonists - amprolium (AM), oxythiamine (OT) or pyrithiamine (PT)...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878225/the-pdk1-inhibitor-dichloroacetate-controls-cholesterol-homeostasis-through-the-erk5-mef2-pathway
#19
Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Sabine Gerbal-Chaloin, Claire Gondeau, Dang-Nghiem Vo, Sana Belkahla, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Milica Bozic, Jose M Valdivielso, Fabienne Bejjani, Isabelle Jariel, Isabel C Lopez-Mejia, Lluis Fajas, Charles-Henri Lecellier, Javier Hernandez, Martine Daujat, Martin Villalba
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878165/mitochondrial-liver-toxicity-of-valproic-acid-and-its-acid-derivatives-is-related-to-inhibition-of-945-lipoamide-dehydrogenase
#20
Alexei P Kudin, Hafiz Mawasi, Arik Eisenkraft, Christian E Elger, Meir Bialer, Wolfram S Kunz
The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM...
September 6, 2017: International Journal of Molecular Sciences
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