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Lactate AND NAD ratio

Leif Hertz, Ye Chen
The 1988 observation by Fox et al. (1988) that brief intense brain activation increases glycolysis (pyruvate formation from glucose) much more than oxidative metabolism has been abundantly confirmed. Specifically glycolytic increase was unexpected because the amount of ATP it generates is much smaller than that formed by subsequent oxidative metabolism of pyruvate. The present article shows that preferential glycolysis can be explained by metabolic processes associated with activation of the glutamate-glutamine cycle...
2017: Frontiers in Integrative Neuroscience
Virender Singh, Raj Kumar Sharma, Thamarailingam Athilingam, Pradip Sinha, Neeraj Sinha, Ashwani Kumar Thakur
Huntington's disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induce HD-like pathologies progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated 1D (1)H NMR spectroscopy-based metabolomics profile of Drosophila HD model...
September 5, 2017: Journal of Proteome Research
Hyun Seung Ban, Bo-Kyung Kim, Hongsub Lee, Hwan Mook Kim, Dipesh Harmalkar, Miso Nam, Song-Kyu Park, Kiho Lee, Joon-Tae Park, Inhyub Kim, Kyeong Lee, Geum-Sook Hwang, Misun Won
HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells...
June 1, 2017: Cell Death & Disease
Enrico Cappelli, Paola Cuccarolo, Giorgia Stroppiana, Maurizio Miano, Roberta Bottega, Vanessa Cossu, Paolo Degan, Silvia Ravera
Energetic metabolism plays an essential role in the differentiation of haematopoietic stem cells (HSC). In Fanconi Anaemia (FA), DNA damage is accumulated during HSC differentiation, an event that is likely associated with bone marrow failure (BMF). One of the sources of the DNA damage is altered mitochondrial metabolism and an associated increment of oxidative stress. Recently, altered mitochondrial morphology and a deficit in the energetic activity in FA cells have been reported. Considering that mitochondria are the principal site of aerobic ATP production, we investigated FA metabolism in order to understand what pathways are able to compensate for this energy deficiency...
March 14, 2017: Biochimica et Biophysica Acta
Jae Mo Park, Chalermchai Khemtong, Shie-Chau Liu, Ralph E Hurd, Daniel M Spielman
PURPOSE: The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD(+) ]. In this study, we assessed the use of hyperpolarized [1-(13) C]alanine and the subsequent detection of the intracellular products of [1-(13) C]pyruvate and [1-(13) C]lactate as a useful substrate for assessing redox levels in the liver in vivo. METHODS: Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion...
May 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
Ibrahim Jalloh, Adel Helmy, Duncan J Howe, Richard J Shannon, Peter Grice, Andrew Mason, Clare N Gallagher, Matthew G Stovell, Susan van der Heide, Michael P Murphy, John D Pickard, David K Menon, T Adrian Carpenter, Peter J Hutchinson, Keri Lh Carpenter
Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-(13)C2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of (13)C-labelled metabolites (six patients)...
July 2017: Journal of Cerebral Blood Flow and Metabolism
Andrew J M Lewis, Jack J J Miller, Chloe McCallum, Oliver J Rider, Stefan Neubauer, Lisa C Heather, Damian J Tyler
Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment on heart and liver pyruvate metabolism in rats in vivo. Both oral treatment for 4 weeks and a single intravenous metformin infusion significantly increased the cardiac [1-(13)C]lactate:[1-(13)C]pyruvate ratio but had no effect on the [1-(13)C]bicarbonate + (13)CO2:[1-(13)C]pyruvate ratio, an index of pyruvate dehydrogenase flux...
December 2016: Diabetes
Chengqian Yin, Dan He, Shuyang Chen, Xiaoling Tan, Nianli Sang
Molecular oxygen is the final electron acceptor in cellular metabolism but cancer cells often become adaptive to hypoxia, which promotes resistance to chemotherapy and radiation. The reduction of endogenous glycolytic pyruvate to lactate is known as an adaptive strategy for hypoxic cells. Whether exogenous pyruvate is required for hypoxic cell proliferation by either serving as an electron acceptor or a biosynthetic substrate remains unclear. By using both hypoxic and ρ0 cells defective in electron transfer chain, we show that exogenous pyruvate is required to sustain proliferation of both cancer and non-cancer cells that cannot utilize oxygen...
July 26, 2016: Oncotarget
Xing Liu, Xu Wang, Jian Tong
Radon and its progeny were confirmed to be a category I carcinogenic agent. However, the molecular basis underlying carcinogenesis induced by radon has not been fully elucidated. Expression of p53, a key regulator in glycolysis, is known to be decreased in carcinogenesis. The aim of this investigation was to determine changes in energy metabolism mediated by p53-related metabolic pathway using radon-induced transformation of human bronchial epithelial (HBE) cells. HBE cells were exposed to radon for 20 min at a concentration of 20,000 Bq/m(3) and cultured for 3 d, and exposed again at the same concentration and duration...
2016: Journal of Toxicology and Environmental Health. Part A
L Liu, Y Wang, R Bai, K Yang, Z Tian
Deregulation of microRNAs in human malignancies has been well documented, among which microRNA-186 (miR-186) has an antiproliferative role in some carcinomas. Here we demonstrate that low expression of miR-186 facilitates aerobic glycolysis in gastric cancer. MiR-186 suppresses cell proliferation induced by hypoxia inducible factor 1 alpha (HIF-1α) in gastric cancer cell lines MKN45 and SGC7901. Cellular glycolysis, including cellular glucose uptake, lactate, ATP/ADP and NAD+/NADH ratios, are also inhibited by miR-186...
May 9, 2016: Oncogenesis
Caixia Wang, Heyu Chen, Mingchao Zhang, Jie Zhang, Xunbin Wei, Weihai Ying
NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, can shuttle the reducing equivalents of cytosolic NADH into mitochondria. It is widely accepted that the major function of NADH shuttles is to increase mitochondrial energy production. Our study tested the hypothesis that the novel major function of NADH shuttles in cancer cells is to maintain glycolysis by decreasing cytosolic NADH/NAD(+) ratios. We found that AOAA, a widely used MAS inhibitor, led to decreased intracellular ATP levels, altered cell cycle and increased apoptosis and necrosis of C6 glioma cells, without affecting the survival of primary astrocyte cultures...
August 1, 2016: Cancer Letters
John Collins, Ting Zhang, Scott Huston, Fangfang Sun, Y-H Percival Zhang, Jinglin Fu
BACKGROUND: Redox cofactors of NADH/NADPH participate in many cellular metabolic pathways for facilitating the electron transfer from one molecule to another in redox reactions. Transhydrogenase plays an important role in linking catabolism and anabolism, regulating the ratio of NADH/NADPH in cells. The cytoplasmic transhydrogenases could be useful to engineer synthetic biochemical pathways for the production of high-value chemicals and biofuels. METHODOLOGY/PRINCIPAL FINDINGS: A transhydrogenase activity was discovered for a FMN-bound diaphorase (DI) from Geobacillus stearothermophilus under anaerobic conditions...
2016: PloS One
Xiao-Dong Zou, Shao-Qing Guo, Zhi-Wei Hu, Wei-Lang Li
Parkinson's disease (PD) is the second most common progressive neurodegenerative movement disorder. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate‑limiting step in the nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in mammals, is a substrate for NAD+‑dependent enzymes, such as sirtuin 1 (SIRT1), and contributes to cell fate decisions. However, the role of NAMPT in PD has remained to be fully elucidated. In the present study, PC12 cells were treated with the neurotoxin 6-hydroxydopamine (6‑OHDA) to establish an in vitro model of PD, following which an obvious inhibitory effect on the levels of NAMPT and NAD+ as well as the NAD+/NADH ratio was detected...
May 2016: Molecular Medicine Reports
Valerio Leoni, Thomas Nury, Anne Vejux, Amira Zarrouk, Claudio Caccia, Meryam Debbabi, Agnès Fromont, Randa Sghaier, Thibault Moreau, Gérard Lizard
In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). α-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis...
May 2017: Journal of Steroid Biochemistry and Molecular Biology
Rebecca Mongeon, Veena Venkatachalam, Gary Yellen
AIM: Cytosolic NADH-NAD(+) redox state is central to cellular metabolism and a valuable indicator of glucose and lactate metabolism in living cells. Here we sought to quantitatively determine NADH-NAD(+) redox in live cells and brain tissue using a fluorescence lifetime imaging of the genetically-encoded single-fluorophore biosensor Peredox. RESULTS: We show that Peredox exhibits a substantial change in its fluorescence lifetime over its sensing range of NADH-NAD(+) ratio...
October 1, 2016: Antioxidants & Redox Signaling
Long Liu, Ningzi Guan, Gexin Zhu, Jianghua Li, Hyun-Dong Shin, Guocheng Du, Jian Chen
Propionic acid (PA) is an important chemical building block widely used in the food, pharmaceutical, and chemical industries. In our previous study, a shuttle vector was developed as a useful tool for engineering Propionibacterium jensenii, and two key enzymes-glycerol dehydrogenase and malate dehydrogenase-were overexpressed to improve PA titer. Here, we aimed to improve PA production further via the pathway engineering of P. jensenii. First, the phosphoenolpyruvate carboxylase gene (ppc) from Klebsiella pneumoniae was overexpressed to access the one-step synthesis of oxaloacetate directly from phosphoenolpyruvate without pyruvate as intermediate...
January 27, 2016: Scientific Reports
Manuel S Godoy, Pablo I Nikel, José G Cabrera Gomez, M Julia Pettinari
The CreBC (carbon source-responsive) two-component regulation system of Escherichia coli affects a number of functions, including intermediary carbon catabolism. The impacts of different creC mutations (a ΔcreC mutant and a mutant carrying the constitutive creC510 allele) on bacterial physiology were analyzed in glucose cultures under three oxygen availability conditions. Differences in the amounts of extracellular metabolites produced were observed in the null mutant compared to the wild-type strain and the mutant carrying creC510 and shown to be affected by oxygen availability...
January 2016: Applied and Environmental Microbiology
Ilkyun Im, Mi-Jin Jang, Seung Ju Park, Sang-Hee Lee, Jin-Ho Choi, Han-Wook Yoo, Seyun Kim, Yong-Mahn Han
A defective mitochondrial respiratory chain complex (DMRC) causes various metabolic disorders in humans. However, the pathophysiology of DMRC in the liver remains unclear. To understand DMRC pathophysiology in vitro, DMRC-induced pluripotent stem cells were generated from dermal fibroblasts of a DMRC patient who had a homoplasmic mutation (m.3398T→C) in the mitochondrion-encoded NADH dehydrogenase 1 (MTND1) gene and that differentiated into hepatocytes (DMRC hepatocytes) in vitro. DMRC hepatocytes showed abnormalities in mitochondrial characteristics, the NAD(+)/NADH ratio, the glycogen storage level, the lactate turnover rate, and AMPK activity...
December 4, 2015: Journal of Biological Chemistry
R Gary Sawers, David P Clark
Pyruvate and acetyl-CoA form the backbone of central metabolism. The nonoxidative cleavage of pyruvate to acetyl-CoA and formate by the glycyl radical enzyme pyruvate formate lyase is one of the signature reactions of mixed-acid fermentation in enterobacteria. Under these conditions, formic acid accounts for up to one-third of the carbon derived from glucose. The further metabolism of acetyl-CoA to acetate via acetyl-phosphate catalyzed by phosphotransacetylase and acetate kinase is an exemplar of substrate-level phosphorylation...
December 2004: EcoSal Plus
Nadia Messaoudi, Valérie Gautier, Julien Dairou, Mouhad Mihoub, Gaëlle Lelandais, Philippe Bouloc, Ahmed Landoulsi, Gilbert Richarme
YajL is the closest prokaryotic homologue of Parkinson's disease-associated DJ-1, a protein of undefined function involved in the oxidative stress response. We reported recently that YajL and DJ-1 protect cells against oxidative stress-induced protein aggregation by acting as covalent chaperones for the thiol proteome, including the NuoG subunit of NADH dehydrogenase 1, and that NADH dehydrogenase 1 activity is negligible in the yajL mutant. We report here that this mutant compensates for low NADH dehydrogenase activity by utilizing NADH-independent alternative dehydrogenases, including pyruvate oxidase PoxB and d-amino acid dehydrogenase DadA, and mixed acid aerobic fermentations characterized by acetate, lactate, succinate and ethanol excretion...
November 2015: Microbiology
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