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Alpha-ketoglutarate

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https://www.readbyqxmd.com/read/29305935/hedgehog-yap-signaling-pathway-regulates-glutaminolysis-to-control-hepatic-stellate-cell-activation
#1
Kuo Du, Jeongeun Hyun, Richard T Premont, Steve S Choi, Gregory A Michelotti, Marzena Swiderska-Syn, George D Dalton, Eric Thelen, Bahar Salimian Rizi, Youngmi Jung, Anna Mae Diehl
BACKGROUND & AIMS: Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP...
January 3, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29289682/l-ascorbic-acid-a-true-substrate-for-hif-proly-hydroxylase
#2
A I Osipyants, A A Poloznikov, N A Smirnova, D M Hushpulian, A Yu Khristichenko, T A Chubar, A A Zakhariants, M Ahuja, I N Gaisina, B Thomas, A M Brown, I G Gazaryan, V I Tishkov
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif...
December 28, 2017: Biochimie
https://www.readbyqxmd.com/read/29281828/the-krebs-cycle-enzyme-isocitrate-dehydrogenase-3a-couples-mitochondrial-metabolism-to-synaptic-transmission
#3
Berrak Ugur, Huan Bao, Michal Stawarski, Lita R Duraine, Zhongyuan Zuo, Yong Qi Lin, G Gregory Neely, Gregory T Macleod, Edwin R Chapman, Hugo J Bellen
Neurotransmission is a tightly regulated Ca2+-dependent process. Upon Ca2+ influx, Synaptotagmin1 (Syt1) promotes fusion of synaptic vesicles (SVs) with the plasma membrane. This requires regulation at multiple levels, but the role of metabolites in SV release is unclear. Here, we uncover a role for isocitrate dehydrogenase 3a (idh3a), a Krebs cycle enzyme, in neurotransmission. Loss of idh3a leads to a reduction of the metabolite, alpha-ketoglutarate (αKG), causing defects in synaptic transmission similar to the loss of syt1...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29277775/novel-metabolically-stable-pca-1-alkbh3-inhibitor-has-potent-antiproliferative-effects-on-du145-cells-in-vivo
#4
Masahiro Ueda, Tadashi Shimizu, Miyuki Mabuchi, Kota Horiike, Kaori Kitae, Hiroaki Hase, Yuko Ueda, Kazutake Tsujikawa, Akito Tanaka
Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects...
January 2018: Anticancer Research
https://www.readbyqxmd.com/read/29230593/effects-of-alpha-ketoglutarate-akg-on-growth-performance-and-non-specific-immunity-of-juvenile-red-drum-fed-diets-with-low-or-adequate-phosphorus-levels
#5
Qiyou Xu, Delbert M Gatlin
This study evaluated the effects of α-ketoglutarate (AKG) on the growth performance, body, and skeletal composition, as well as non-specific immunity of juvenile red drum (Sciaenops ocellatus) fed adequate or low-phosphorus diets. A 2 × 2 factorial design was arranged with two levels of total phosphorus (1.0 or 1.6%) and two levels (0 or 1%) of AKG. Each diet was fed to red drum in four replicate 110-L aquaria (15 fish/aquarium) twice daily for 7 weeks. The results indicated that the low-P diets significantly (P < 0...
December 11, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/29223816/cortex-and-hippocampus-dna-epigenetic-response-to-a-long-term-arsenic-exposure-via-drinking-water
#6
Xiaoyan Du, Meiping Tian, Xiaoxue Wang, Jie Zhang, Qingyu Huang, Liangpo Liu, Heqing Shen
The neurotoxicity of arsenic is a serious health problem, especially for children. DNA epigenetic change may be an important pathogenic mechanism, but the molecular pathway remains obscure. In this study, the weaned male Sprague-Dawly (SD) rats were treated with arsenic trioxide via drinking water for 6 months, simulating real developmental exposure situation of children. Arsenic exposure impaired the cognitive abilities, and altered the expression of neuronal activity-regulated genes. Total arsenic concentrations of cortex and hippocampus tissues were significantly increased in a dose-dependent manner...
December 7, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/29222329/glutaminolysis-is-required-for-tgf-%C3%AE-1-induced-myofibroblast-differentiation-and-activation
#7
Karen Bernard, Naomi J Logsdon, Gloria A Benavides, Yan Sanders, Jianhua Zhang, Victor M Darley-Usmar, Victor J Thannickal
Myofibroblasts participate in physiological wound healing and pathological fibrosis.  Myofibroblast differentiation is characterized by the expression of alpha-smooth muscle actin (α-SMA) and extracellular matrix (ECM) proteins, and is dependent on metabolic reprogramming.  In this study, we explored the role of glutaminolysis and metabolites of the tricarboxylic acid cycle (TCA) in supporting myofibroblast differentiation.  Glutaminolysis converts glutamine (Gln) into alpha-ketoglutarate (α-KG), a critical intermediate in the TCA cycle...
December 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29214991/pseudomonas-aeruginosa-zinc-uptake-in-chelating-environment-is-primarily-mediated-by-the-metallophore-pseudopaline
#8
Sébastien Lhospice, Nicolas Oswaldo Gomez, Laurent Ouerdane, Catherine Brutesco, Ghassan Ghssein, Christine Hajjar, Ahmed Liratni, Shuanglong Wang, Pierre Richaud, Sophie Bleves, Geneviève Ball, Elise Borezée-Durant, Ryszard Lobinski, David Pignol, Pascal Arnoux, Romé Voulhoux
Metal uptake is vital for all living organisms. In metal scarce conditions a common bacterial strategy consists in the biosynthesis of metallophores, their export in the extracellular medium and the recovery of a metal-metallophore complex through dedicated membrane transporters. Staphylopine is a recently described metallophore distantly related to plant nicotianamine that contributes to the broad-spectrum metal uptake capabilities of Staphylococcus aureus. Here we characterize a four-gene operon (PA4837-PA4834) in Pseudomonas aeruginosa involved in the biosynthesis and trafficking of a staphylopine-like metallophore named pseudopaline...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29191830/lipoic-acid-metabolism-and-mitochondrial-redox-regulation
#9
Ashley D Solmonson, Ralph J DeBerardinis
Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multi-enzyme complexes...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29190890/administration-of-alpha-ketoglutarate-improves-epithelial-restitution-under-stress-injury-in-early-weaning-piglets
#10
Liuqin He, Xihong Zhou, Niu Huang, Huan Li, Zhijie Cui, Junquan Tian, Qian Jiang, Shaojuan Liu, Jian Wu, Tiejun Li, Kang Yao, Yulong Yin
Alpha-ketoglutarate (AKG) is an important cellular metabolite that participates in energy production and amino acid metabolism. However, the protective effects and mechanism of AKG on mucosal lesions have not been well understood. This study was conducted to investigate the effects of dietary AKG supplementation on epithelial restitution in early-weaning piglets under Escherichia coli lipopolysaccharide (LPS) induction. A total of 32 weaned piglets were used in a 2 × 2 factorial design; the major factors were dietary treatment (basal diet or AKG diet) and inflammatory challenge (LPS or saline)...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29181198/effects-of-long-term-cultivation-on-medium-with-alpha-ketoglutarate-supplementation-on-metabolic-processes-of-saccharomyces-cerevisiae
#11
Nadia Burdyliuk, Maria Bayliak
During last years, alpha-ketoglutarate (AKG), an important intermediate in the Krebs cycle, has been intensively studied as a dietary supplement with stress-protective and potential antiaging effects. Here, we examined the effects of exogenous AKG on metabolic processes and survival of yeast Saccharomyces cerevisiae during long-term cultivation. Growth on AKG had no effect on the total cell number but increased the number of reproductively active cells at the late days of cultivation (from day 7 to day 15)...
2017: Journal of Aging Research
https://www.readbyqxmd.com/read/29158345/stable-oxidative-cytosine-modifications-accumulate-in-cardiac-mesenchymal-cells-from-type2-diabetes-patients-rescue-by-alpha-ketoglutarate-and-tet-tdg-functional-reactivation
#12
Francesco Spallotta, Chiara Cencioni, Sandra Atlante, Davide Garella, Mattia Cocco, Mattia Mori, Raffaella Mastrocola, Carsten Künne, Stefan Günther, Simona Nanni, Valerio Azzimato, Sven Zukunft, Angela Kornberger, Duran Sueruen, Frank Schnutgen, Harald von Melchner, Antonella Di Stilo, Manuela Aragno, Maarten Braspenning, Wim Van Criekinge, Miles J De Blasio, Rebecca H Ritchie, Germana Zaccagnini, Fabio Martelli, Antonella Farsetti, Ingrid Fleming, Thomas Braun, Andres Beiras-Fernandez, Bruno Botta, Massimo Collino, Massimo Bertinaria, Andreas M Zeiher, Carlo Gaetano
Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically-relevant primary cell population. Diabetes compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epi-metabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs)...
November 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#13
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29114580/alpha-ketoglutarate-protects-streptomyces-coelicolor-from-visible-light-induced-phototoxicity
#14
Feng Xu, Jin Wang, Guo-Ping Zhao
It has been known that some Streptomyces species, including the model strain Streptomyces coelicolor, are vulnerable to visible light. Much evidence demonstrated that the phototoxicity induced by visible light is a consequence of the formation of intracellular reactive oxygen species (ROS), which are potentially harmful to cells. In this study, we found that α-ketoglutarate (α-KG) has a protective role against the phototoxicity in S. coelicolor. It could be because that α-KG can detoxify the ROS with the concomitant formation of succinate, which mediates the cells getting into anaerobiosis to produce more NADH and maintain intracellular redox homeostasis, a situation that was demonstrated by overexpressing gdhA in S...
March 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/29107960/glutamine-deficiency-induces-dna-alkylation-damage-and-sensitizes-cancer-cells-to-alkylating-agents-through-inhibition-of-alkbh-enzymes
#15
Thai Q Tran, Mari B Ishak Gabra, Xazmin H Lowman, Ying Yang, Michael A Reid, Min Pan, Timothy R O'Connor, Mei Kong
Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death...
November 2017: PLoS Biology
https://www.readbyqxmd.com/read/29091971/the-effect-of-respiration-buffer-composition-on-mitochondrial-metabolism-and-function
#16
Lucas C Wollenman, Matthew R Vander Ploeg, Mackinzie L Miller, Yizhu Zhang, Jason N Bazil
Functional studies on isolated mitochondria critically rely on the right choice of respiration buffer. Differences in buffer composition can lead to dramatically different respiration rates leading to difficulties in comparing prior studies. The ideal buffer facilities high ADP-stimulated respiratory rates and minimizes substrate transport effects so that the ability to distinguish between various treatments and conditions is maximal. In this study, we analyzed a variety of respiration buffers and substrate combinations to determine the optimal conditions to support mitochondrial function through ADP-stimulated respiration and uncoupled respiration using FCCP...
2017: PloS One
https://www.readbyqxmd.com/read/29089260/design-synthesis-and-biological-activity-of-3-pyrazine-2-yl-oxazolidin-2-ones-as-novel-potent-and-selective-inhibitors-of-mutant-isocitrate-dehydrogenase-1
#17
Tianfang Ma, Fangxia Zou, Stefan Pusch, Lijun Yang, Qihua Zhu, Yungen Xu, Yueqing Gu, Andreas von Deimling, Xiaoming Zha
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia, emerging as an attractive antitumor target. In order to discovery potent new mutant IDH1 inhibitors, we designed, synthesized and evaluated a series of allosteric mIDH1 inhibitors harboring the scaffold of 3-pyrazine-2-yl-oxazolidin-2-ones...
October 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29076432/the-alkb-family-of-fe-ii-alpha-ketoglutarate-dependent-dioxygenases-modulate-embryogenesis-through-epigenetic-regulation
#18
Yuting Liu, Liang Xie, Quan Yuan
BACKGROUND: The study of epigenetic regulation has made substantial progress in recent years. The AlkB family in E. coli was identified as a type of DNA repair enzyme that removes alkyl adducts from nucleobases. Recently, nine mammalian homologs, ALKBH1-9, have been successfully identified and defined as diverse demethylases. ALKBH1, ALKBH5, ALKBH8 and ALKBH9 act as RNA demethylases, while ALKBH2-3 and ALKBH7 correct methyl and etheno adducts in DNA. Moreover, ALKBH4 focuses primarily on actin...
October 26, 2017: Current Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29050286/a-prospective-study-of-serum-metabolites-and-glioma-risk
#19
Jiaqi Huang, Stephanie J Weinstein, Cari M Kitahara, Edward D Karoly, Joshua N Sampson, Demetrius Albanes
Malignant glioma is one of the most lethal adult cancers, yet its etiology remains largely unknown. We conducted a prospective serum metabolomic analysis of glioma based on 64 cases and 64 matched controls selected from Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from collection of baseline fasting serum to diagnosis was nine years (inter-decile range 3-20 years). LC/MS-MS identified 730 known metabolites, and conditional logistic regression models estimated odds ratios for one-standard deviation differences in log-metabolite signals...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29040866/carbon-dependent-alleviation-of-ammonia-toxicity-for-algae-cultivation-and-associated-mechanisms-exploration
#20
Qian Lu, Paul Chen, Min Addy, Renchuan Zhang, Xiangyuan Deng, Yiwei Ma, Yanling Cheng, Fida Hussain, Chi Chen, Yuhuan Liu, Roger Ruan
Ammonia toxicity in wastewater is one of the factors that limit the application of algae technology in wastewater treatment. This work explored the correlation between carbon sources and ammonia assimilation and applied a glucose-assisted nitrogen starvation method to alleviate ammonia toxicity. In this study, ammonia toxicity to Chlorella sp. was observed when NH3-N concentration reached 28.03mM in artificial wastewater. Addition of alpha-ketoglutarate in wastewater promoted ammonia assimilation, but low utilization efficiency and high cost of alpha-ketoglutarate limits its application in wastewater treatment...
September 28, 2017: Bioresource Technology
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