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Glutaminase

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https://www.readbyqxmd.com/read/29343523/a-novel-l-asparaginase-with-low-l-glutaminase-coactivity-is-highly-efficacious-against-both-t-and-b-cell-acute-lymphoblastic-leukemias-in-vivo
#1
Hien Anh Nguyen, Ying Su, Jenny Yu Zhang, Aleksandar Antanasijevic, Michael Caffrey, Amanda M Schalk, Li Liu, Damiano Rondelli, Annie Oh, Dolores L Mahmud, Maarten C Bosland, Andre Kajdacsy-Balla, Sofie Peirs, Tim Lammens, Veerle Mondelaers, Barbara De Moerloose, Steven Goossens, Michael J Schlicht, Kasim K Kabirov, Alexander V Lyubimov, Bradley J Merrill, Yogen Saunthararajah, Pieter Van Vlierberghe, Arnon Lavie
Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug L-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine-dependency of ALL cells. In addition to hydrolyzing the amino acid L-asparagine, all FDA-approved L-asparaginases also have significant L-glutaminase coactivity. Since several reports suggest that L-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced L-glutaminase coactivity might be clinically beneficial if their anti-leukemic activity would be preserved...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29337138/let-7-suppresses-b-cell-activation-through-restricting-the-availability-of-necessary-nutrients
#2
Shuai Jiang, Wei Yan, Shizhen Emily Wang, David Baltimore
The control of uptake and utilization of necessary extracellular nutrients-glucose and glutamine-is an important aspect of B cell activation. Let-7 is a family of microRNAs known to be involved in metabolic control. Here, we employed several engineered mouse models, including B cell-specific overexpression of Lin28a or the let-7a-1/let-7d/let-7f-1 cluster (let-7adf) and knockout of individual let-7 clusters to show that let-7adf specifically inhibits T cell-independent (TI) antigen-induced immunoglobulin (Ig)M antibody production...
January 10, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29323154/effects-of-metformin-on-colorectal-cancer-stem-cells-depend-on-alterations-in-glutamine-metabolism
#3
Jae Hyun Kim, Kyoung Jin Lee, Yoojeong Seo, Ji-Hee Kwon, Jae Pil Yoon, Jo Yeon Kang, Hyun Jung Lee, Soo Jung Park, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim, Tae Ii Kim
Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29319172/long-non-coding-rna-hotair-acts-as-a-competing-endogenous-rna-to-promote-glioma-progression-by-sponging-mir-126-5p
#4
Liang Liu, Sitong Cui, Teng Wan, Xiaojian Li, Wei Tian, Rui Zhang, Liangsheng Luo, Yan Shi
LncRNA HOX transcript antisense intergenic RNA (HOTAIR) has been shown to play prominent roles in tumorigenesis. However, its precise molecular mechanism in glioma has not been completely elucidated. In this study, we found that HOTAIR was aberrantly up-regulated in glioma tissues and was negatively correlated with miR-126-5p expression. Next, we determined that HOTAIR promote glioma progression by sponging miR-126-5p. Subsequently, glutaminase (GLS) was confirmed to be a direct target of miR-126-5p using bioinformatics software and a luciferase reporter assay...
January 10, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29317493/characterization-of-the-interactions-of-potent-allosteric-inhibitors-with-glutaminase-c-a-key-enzyme-in-cancer-cell-glutamine-metabolism
#5
Qingqiu Huang, Clint Stalnecker, Chengliang Zhang, Lee A McDermott, Prema Iyer, Jason O'Neill, Shawn Reimer, Richard A Cerione, William P Katt
Altered glycolytic flux in cancer cells (the Warburg effect) causes their proliferation to rely upon elevated glutamine metabolism (glutamine addiction). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small molecule CB-839 was reported to be more potent than other allosteric GAC inhibitors, including the parent compound BPTES, and is in clinical trials. Recently, we described the synthesis of BPTES analogs having distinct saturated heterocyclic cores as a replacement for the flexible chain moiety, with improved microsomal stability relative to CB-839 and BPTES...
January 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29305935/hedgehog-yap-signaling-pathway-regulates-glutaminolysis-to-control-hepatic-stellate-cell-activation
#6
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/29298131/a-systematic-review-of-p53-regulation-of-oxidative-stress-in-skeletal-muscle
#7
Kaitlyn Beyfuss, David A Hood
BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases...
January 3, 2018: Redox Report: Communications in Free Radical Research
https://www.readbyqxmd.com/read/29288802/increasing-extracellular-cgmp-in-cerebellum-in-vivo-reduces-neuroinflammation-gabaergic-tone-and-motor-in-coordination-in-hyperammonemic-rats
#8
Andrea Cabrera-Pastor, Tiziano Balzano, Vicente Hernández-Rabaza, Michele Malaguarnera, Marta Llansola, Vicente Felipo
Hyperammonemia is a main contributor to cognitive impairment and motor in-coordination in patients with hepatic encephalopathy. Hyperammonemia-induced neuroinflammation mediates the neurological alterations in hepatic encephalopathy. Intracerebral administration of extracellular cGMP restores some but not all types of cognitive impairment. Motor in-coordination, is mainly due to increased GABAergic tone in cerebellum. We hypothesized that extracellular cGMP would restore motor coordination in hyperammonemic rats by normalizing GABAergic tone in cerebellum and that this would be mediated by reduction of neuroinflammation...
December 27, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29277233/comparison-of-kokumi-%C3%AE-glu-n-1-val-and-%C3%AE-glu-n-1-met-synthesized-through-transpeptidation-catalyzed-by-glutaminase-from-bacillus-amyloliquefaciens
#9
Juan Yang, Dongxiao Sun-Waterhouse, Jin Xie, Lan Wang, Hong-Zhang Chen, Chun Cui, Mouming Zhao
A series of γ-[Glu](n=2,3,4)-Val or γ-[Glu](n=2,3,4)-Met were synthesized in the presence of donor (Gln) and corresponding acceptor (Val or Met) through transpeptidation catalyzed by the glutaminase from Bacillus amyloliquefaciens. Gln in excess significantly (p < .05) improved the yield of γ-[Glu](n>1)-Val/Met except for γ-Glu-Val/Met. The Km values for transpeptidase activity to yield γ-[Glu](n=0,1,2,3)-Val increased with an elevated n, but remained essentially the same irrespective of n value for γ-[Glu](n=0,1,2)-Met (which were 31-44% of that for γ-[Glu]3-Met)...
May 1, 2018: Food Chemistry
https://www.readbyqxmd.com/read/29273324/temporal-expression-of-c-fos-and-genes-coding-for-neuropeptides-and-enzymes-of-amino-acid-and-amine-neurotransmitter-biosynthesis-in-retina-pineal-and-hypothalamus-of-a-migratory-songbird-evidence-for-circadian-rhythm-dependent-seasonal-responses
#10
Ila Mishra, Devraj Singh, Vinod Kumar
This study investigated whether, in photoperiodic songbirds, the circadian pacemaker system (CPS) connects to the seasonal photoperiodic responses, by changes at transcriptional level in the level and 24-h rhythm of its constituent neurotransmitters. We used blackheaded buntings (Emberiza melanocephala), which exhibits distinct seasonal states in captivity under appropriate photoperiods and hence served as a useful model system. Under short days, buntings remain in the photosensitive state (winter phenotype: non-migratory, non-breeding)...
December 19, 2017: Neuroscience
https://www.readbyqxmd.com/read/29222329/glutaminolysis-is-required-for-tgf-%C3%AE-1-induced-myofibroblast-differentiation-and-activation
#11
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/29215843/-influence-of-partial-hepatectomie-on-ammoniumdetoxications-function-of-liver-at-chronic-tetrachlorcarbon-hepatitis
#12
P N Savilov
The purpose. To study the effect of partial hepatectomy (PH) on the main ways of ammonia detoxication in the liver (synthesis of urea and glutamine) in chronic tetrachlorcarbon (CCl4) hepatitis. Methods. The experiments were performed on 165 white outbred rats (females) weighing 180-220 g Chronic CCl4-hepatitis was reproduced by subcutaneous injection of 50% CCl4 solution in olive oil (0.1 ml/100g of body weight,65 days, through the day with two two-week breaks between 6-7 and 13-14 injections). PH conducted electrocautery, removing part of the left lobe of the liver (15-20% by weight of the body) to 65th (and last) day of the introduction of the CCl4...
April 2017: Patologicheskaia Fiziologiia i èksperimental'naia Terapiia
https://www.readbyqxmd.com/read/29212209/targeted-inhibition-of-glutaminase-as-a-potential-new-approach-for-the-treatment-of-nf1-associated-soft-tissue-malignancies
#13
Tahir N Sheikh, Parag P Patwardhan, Serge Cremers, Gary K Schwartz
Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in NF1 associated tumors has never been studied. We report for the first time, a strong correlation between the NF1 status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29209449/effect-of-oleanolic-acid-on-small-intestine-morphology-and-enzymes-of-glutamine-metabolism-in-diabetic-rats
#14
Murtala Bindawa Isah, Bubuya Masola
The small intestine (SI) is the main site for food absorption and glutamine utilization hence critical in metabolic disorders that involve energy balance such as diabetes. This study investigates the effects of oleanolic acid (OA) on SI morphology and some enzymes of glutamine metabolism in male Sprague-Dawley diabetic rats. High dose STZ-induced diabetes (HDD) and low dose STZ-induced diabetes (LDD) were induced by intraperitoneal injection of 60 and 40 mg streptozotocin/kg body weight respectively. Non-diabetic and diabetic rats were treated for two weeks with OA, insulin or OA + insulin in HDD study while animals in the in LDD study were treated with OA...
2017: International Journal of Physiology, Pathophysiology and Pharmacology
https://www.readbyqxmd.com/read/29208682/the-receptor-tyrosine-kinase-epha2-promotes-glutamine-metabolism-in-tumors-by-activating-the-transcriptional-coactivators-yap-and-taz
#15
Deanna N Edwards, Verra M Ngwa, Shan Wang, Eileen Shiuan, Dana M Brantley-Sieders, Laura C Kim, Albert B Reynolds, Jin Chen
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer...
December 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/29187839/the-glutaminase-dependent-system-confers-extreme-acid-resistance-to-new-species-and-atypical-strains-of-brucella
#16
Luca Freddi, Maria A Damiano, Laurent Chaloin, Eugenia Pennacchietti, Sascha Al Dahouk, Stephan Köhler, Daniela De Biase, Alessandra Occhialini
Neutralophilic bacteria have developed specific mechanisms to cope with the acid stress encountered in environments such as soil, fermented foods, and host compartments. In Escherichia coli, the glutamate decarboxylase (Gad)-dependent system is extremely efficient: it requires the concerted action of glutamate decarboxylase (GadA/GadB) and of the glutamate (Glu)/γ-aminobutyrate antiporter, GadC. Notably, this system is operative also in new strains/species of Brucella, among which Brucella microti, but not in the "classical" species, with the exception of marine mammals strains...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29170516/metabolic-differences-in-glutamine-utilization-lead-to-metabolic-vulnerabilities-in-prostate-cancer
#17
Niki Marie Zacharias, Christopher McCullough, Sriram Shanmugavelandy, Jaehyuk Lee, Youngbok Lee, Prasanta Dutta, James McHenry, Linda Nguyen, William Norton, Lawrence W Jones, Pratip K Bhattacharya
The new oncologic paradigm of precision medicine is focused on identifying metabolic, proteomic, transcriptomic and genomic variabilities in tumors that can be exploited to tailor treatments and improve patient outcomes. Metabolic changes are a hallmark of cancer, and inhibition of metabolic pathways is now a major strategy in medicinal chemistry for targeting cancers. However, non-invasive biomarkers to categorize metabolic subtypes are in short supply. The purpose of this study was to characterize the intracellular and extracellular metabolic profiles of four prostate cancer cell lines with varying degrees of aggressiveness...
November 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29169183/myc-regulation-of-glutamine-proline-regulatory-axis-is-key-in-luminal-b-breast-cancer
#18
Madeleine L Craze, Hayley Cheung, Natasha Jewa, Nuno D M Coimbra, Daniele Soria, Rokaya El-Ansari, Mohammed A Aleskandarany, Kiu Wai Cheng, Maria Diez-Rodriguez, Christopher C Nolan, Ian O Ellis, Emad A Rakha, Andrew R Green
BACKGROUND: Altered cellular metabolism is a hallmark of cancer and some are reliant on glutamine for sustained proliferation and survival. We hypothesise that the glutamine-proline regulatory axis has a key role in breast cancer (BC) in the highly proliferative classes. METHODS: Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1), and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large, well-characterised cohorts...
November 23, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29167114/exocrine-pancreas-glutamate-secretion-help-to-sustain-enterocyte-nutritional-needs-under-protein-restriction
#19
Selene Araya, Evelyne Kuster, Dino Gluch, Luca Mariotta, Christian Lutz, Theresia V Reding, Rolf Graf, François Verrey, Simone M R Camargo
Glutamine (Gln) is the most concentrated amino acid in blood and considered conditionally essential. Its requirement is increased during physiological stress, such as malnutrition or illness, despite its production by muscle and other organs. In the malnourished state Gln has been suggested to have a trophic effect on the exocrine pancreas and small intestine. However, the Gln transport capacity, the functional relationship of these two organs and the potential role of the Gln-glutamate (Glu) cycle are unknown...
November 22, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29163707/n-myc-downstream-regulated-gene-2-restrains-glycolysis-and-glutaminolysis-in-clear-cell-renal-cell-carcinoma
#20
Wei Shi, Xinyuan Xu, Fei Yan, Bao Wang, Hang Zhao, Aaron Chan, Zhen Ren, Yongzheng Ma, Fuli Wang, Jianlin Yuan
Glycolysis and glutaminolysis are heavily involved in the metabolic reprogramming of cancer cells. The activation of oncogenes and inactivation of tumor suppressor genes has a marked effect on the cellular metabolic processes glycolysis and glutaminolysis. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that previous studies have demonstrated can inhibit the growth, proliferation and metastasis of clear cell renal cell carcinoma (ccRCC) cells. However, the function of NDRG2 in ccRCC metabolism remains unknown...
December 2017: Oncology Letters
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