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Lactate AND NAD ratio

Kurt-Wolfram Sühs, Natalia Novoselova, Maike Kuhn, Lena Seegers, Volkhard Kaever, Kirsten Müller-Vahl, Corinna Trebst, Thomas Skripuletz, Martin Stangel, Frank Pessler
Background: The tryptophan-kynurenine-NAD+ pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in CNS infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers. Methods: We measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 220 cerebrospinal fluid samples from patients with bacterial and viral (herpes simplex, varicella zoster, enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (anti-NMDA-R encephalitis, multiple sclerosis), and noninflamed controls (Bell's palsy, normal pressure hydrocephalus, Tourette syndrome)...
February 5, 2019: Journal of Infectious Diseases
Chenglai Xia, Zhihong He, Shaofen Liang, Ruihong Chen, Weikang Xu, Jie Yang, Guohong Xiao, Shibo Jiang
The molecular mechanisms underlying the antineoplastic properties of metformin combined with nelfinavir remain elusive. To explore this question, transmission electron microscopy (TEM) was used to observe the combinatorial effect of inducing autophagosome formation in human cervical cancer cells. Western blotting respectively assayed protein expression of LC3I, LC3II, Beclin-1, Autophagy-related protein 7 (Atg7), Autophagy-related protein 3 (Atg3), NAD-dependent deacetylase sirtuin-3 (SIRT3) and major histocompatibility complex class I chain-related gene A (MICA)...
January 26, 2019: European Journal of Pharmacology
Wondong Kim, Amy Deik, Clicerio Gonzalez, Maria Elena Gonzalez, Feifei Fu, Michele Ferrari, Claire L Churchhouse, Jose C Florez, Suzanne B R Jacobs, Clary B Clish, Eugene P Rhee
The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD+ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD+ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD+ /NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD+ recycling is acutely adaptive when aerobic respiration is impaired in vivo...
January 14, 2019: Cell Metabolism
Ahmed Alshawi, Loranne Agius
The mechanisms by which metformin (dimethylbiguanide) inhibits hepatic gluconeogenesis at concentrations relevant for type 2 diabetes therapy remain debated.  Two proposed mechanisms are:  inhibition of mitochondrial Complex 1 with consequent compromised ATP and AMP homeostasis; or inhibition of mitochondrial glycerophosphate dehydrogenase (mGPDH) and thereby attenuated transfer of reducing equivalents from the cytoplasm to mitochondria resulting in a raised lactate/pyruvate ratio and redox-dependent inhibition of gluconeogenesis from reduced but not oxidised substrates...
December 27, 2018: Journal of Biological Chemistry
S Wang, Z-Y Cheng, X-J Chen, H-Z Xue
OBJECTIVE: The aim of the study was to explore the pharmacological role of ulinastatin in rats with myocardium infarction (MI) and its underlying mechanism. MATERIALS AND METHODS: Rats were randomly assigned into sham group, MI group, and ulinastatin group, with 8 rats in each group. MI model in rats was constructed and specific drug administrations were performed in each group. Electrocardiogram and hemodynamics were detected before and after animal procedures...
December 2018: European Review for Medical and Pharmacological Sciences
Ross A Kelly, Joseph Leedale, Andy Harrell, Daniel A Beard, Laura E Randle, Amy E Chadwick, Steven D Webb
Cancer cells depend on glucose metabolism via glycolysis as a primary energy source, despite the presence of oxygen and fully functioning mitochondria, in order to promote growth, proliferation and longevity. Glycolysis relies upon NAD+ to accept electrons in the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction, linking the redox state of the cytosolic NAD+ pool to glycolytic rate. The free cytosolic NAD+/NADH ratio is involved in over 700 oxidoreductive enzymatic reactions and as such, the NAD+/NADH ratio is regarded as a metabolic readout of overall cellular redox state...
2018: PloS One
Min Yan, Huan Qi, Tian Xia, Xinjie Zhao, Wen Wang, Zhichao Wang, Chang Lu, Zhen Ning, Huan Chen, Tongming Li, Dinesh Singh Tekcham, Xiumei Liu, Jing Liu, Di Chen, Xiaolong Liu, Guowang Xu, Hai-Long Piao
BACKGROUND: Metformin is a first-line drug for treating type 2 diabetes and has gained considerable interest as a potential anticancer agent. Increasing evidence suggests that metformin antagonizes diabetes and tumors through disrupting metabolic homeostasis and altering energy state. However, whether AMP activated protein kinase (AMPK) contributes to such effects of metformin remains controversial. METHODS: We performed integrative metabolomics analyses to systematically examine the effects of metformin on metabolic pathways in Prkaa1 wild type (WT) and knock-out (KO) mouse embryonic fibroblast (MEF) cells as well as human cells based on gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry (CE-MS)...
November 20, 2018: Metabolism: Clinical and Experimental
Antonio Sueiti Maeda Júnior, Jorgete Constantin, Karina Sayuri Utsunomiya, Eduardo Hideo Gilglioni, Fabiana Rodrigues Silva Gasparin, Fernando Olinto Carreño, Solange Marta Franzói de Moraes, Márcio Rocha, Maria Raquel Marçal Natali, Cristiane Vizioli de Castro Ghizoni, Adelar Bracht, Emy Luiza Ishii-Iwamoto, Rodrigo Polimeni Constantin
Gluconeogenesis overstimulation due to hepatic insulin resistance is the best-known mechanism behind elevated glycemia in obese subjects with hepatic steatosis. This suggests that glucose production in fatty livers may differ from that of healthy livers, also in response to other gluconeogenic determinant factors, such as the type of substrate and modulators. Thus, the aim of this study was to investigate the effects of these factors on hepatic gluconeogenesis in cafeteria diet-induced obese adult rats submitted to a cafeteria diet at a young age...
October 23, 2018: Nutrients
Yuki Doi
Bacterial lactate production by fermentative lactate dehydrogenase is generally activated under anaerobic conditions. However, when the Enterococcus faecalis strain W11 was cultured with a high concentration of glycerol (1.0 M), but not with glucose, up to 0.95 M L-lactate was produced from 1.0 M glycerol via the fermentative L-lactate dehydrogenase (LdhL1) reaction despite the abundant supply of oxygen. To understand the underlying mechanism, transcription, metabolic products, and intracellular NADH/total NAD (tNAD) ratio of W11 were analyzed...
September 19, 2018: Applied Microbiology and Biotechnology
Ling-Fang Wang, Cong-Cong Huang, Yun-Fei Xiao, Xiao-Hui Guan, Xiao-Nv Wang, Qing Cao, Yu Liu, Xuan Huang, Li-Bin Deng, Ke-Yu Deng, Hong-Bo Xin
BACKGROUND/AIMS: Previous studies showed that CD38 deficiency protected heart from ischemia/reperfusion injury and high fat diet (HFD)-induced obesity in mice. However, the role of CD38 in HFD-induced heart injury remains unclear. In the present study, we have investigated the effects and mechanisms of CD38 deficiency on HFD-induced heart injury. METHODS: The metabolites in heart from wild type (WT) and CD38 knockout (CD38-/-) mice were examined using metabolomics analysis...
2018: Cellular Physiology and Biochemistry
Matthew G Stovell, Marius O Mada, Adel Helmy, T Adrian Carpenter, Eric P Thelin, Jiun-Lin Yan, Mathew R Guilfoyle, Ibrahim Jalloh, Duncan J Howe, Peter Grice, Andrew Mason, Susan Giorgi-Coll, Clare N Gallagher, Michael P Murphy, David K Menon, Peter J Hutchinson, Keri L H Carpenter
A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31 P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days)...
July 24, 2018: Scientific Reports
Md Mahdi Hasan-Olive, Knut H Lauritzen, Mohammad Ali, Lene Juel Rasmussen, Jon Storm-Mathisen, Linda H Bergersen
A ketogenic diet (KD; high-fat, low-carbohydrate) can benefit refractory epilepsy, but underlying mechanisms are unknown. We used mice inducibly expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) to cause progressive mitochondrial dysfunction selectively in forebrain neurons. We examined the levels of mRNAs and proteins crucial for mitochondrial biogenesis and dynamics. We show that hippocampal pyramidal neurons in mutUNG1 mice, as well as cultured rat hippocampal neurons and human fibroblasts with H2 O2 induced oxidative stress, improve markers of mitochondrial biogenesis, dynamics and function when fed on a KD, and when exposed to the ketone body β-hydroxybutyrate, respectively, by upregulating PGC1α, SIRT3 and UCP2, and (in cultured cells) increasing the oxygen consumption rate (OCR) and the NAD+ /NADH ratio...
July 19, 2018: Neurochemical Research
L Han, F Batistel, Y Ma, A S M Alharthi, C Parys, J J Loor
The periparturient period is the most critical period during the lactation cycle of dairy cows and is characterized by increased oxidative stress status. The objective of this experiment was to evaluate the effect of supplementing rumen-protected methionine on nuclear factor erythroid 2-like 2 (NFE2L2, formerly NRF2) protein and target gene expression in the mammary gland during the early postpartal period. Multiparous Holstein cows were used in a block design experiment with 30 cows per treatment. Treatments consisting of a basal control diet (control) or the basal diet plus rumen-protected methionine (methionine) were fed from d -28 to 60 relative to parturition...
September 2018: Journal of Dairy Science
Xiaoshan Zhou, Sophie Curbo, Fuqiang Li, Shuba Krishnan, Anna Karlsson
BACKGROUND: Glutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to support long-term cell proliferation. The aim of the present study was to address the role of GOT1 in the metabolic adaption of cancer cells. METHODS: GOT1-null and knockdown cell lines were established through CRISPR/Cas9 and shRNA techniques...
May 11, 2018: BMC Cancer
L Q Han, Z Zhou, Y Ma, F Batistel, J S Osorio, J J Loor
Changes in the production of reactive oxygen species in the mammary gland of dairy cows during the periparturient period could lead to oxidative stress and potentially impair mammary function. Phosphorylation of the transcription factor nuclear factor erythroid 2-like 2 (NFE2L2), also known as nuclear factor-E2-related factor 2, controls mRNA abundance of genes encoding antioxidant proteins and enzymes. The hypothesis was that NFE2L2 phosphorylation status and target gene mRNA abundance in the mammary gland of dairy cows is altered around parturition...
July 2018: Journal of Dairy Science
Adolf M Sandbichler, Bianca Jansen, Bettina A Peer, Monika Paulitsch, Bernd Pelster, Margit Egg
BACKGROUND/AIMS: Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. METHODS: For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts...
2018: Cellular Physiology and Biochemistry
Joe T Sharick, Peter F Favreau, Amani A Gillette, Sophia M Sdao, Matthew J Merrins, Melissa C Skala
While NAD(P)H fluorescence lifetime imaging (FLIM) can detect changes in flux through the TCA cycle and electron transport chain (ETC), it remains unclear whether NAD(P)H FLIM is sensitive to other potential fates of glucose. Glucose carbon can be diverted from mitochondria by the pentose phosphate pathway (via glucose 6-phosphate dehydrogenase, G6PDH), lactate production (via lactate dehydrogenase, LDH), and rejection of carbon from the TCA cycle (via pyruvate dehydrogenase kinase, PDK), all of which can be upregulated in cancer cells...
April 3, 2018: Scientific Reports
Romain Irague, Christopher M Topham, Nelly Martineau, Audrey Baylac, Clément Auriol, Thomas Walther, Jean-Marie François, Isabelle André, Magali Remaud-Siméon
An end-point ADP/NAD+ acid/alkali assay procedure, directly applicable to library screening of any type of ATP-utilising/ADP producing enzyme activity, was implemented. Typically, ADP production is coupled to NAD+ co-enzyme formation by the conventional addition of pyruvate kinase and lactate dehydrogenase. Transformation of enzymatically generated NAD+ into a photometrically active alkali derivative product is then achieved through the successive application of acidic/alkali treatment steps. The assay was successfully miniaturized to search for malate kinase activity in a structurally-guided library of LysC aspartate kinase variants comprising 6,700 clones...
2018: PloS One
Divya Murthy, Enza Vernucci, Gennifer Goode, Jaime Abrego, Pankaj K Singh
Hypoxia is frequently observed in human cancers and induces global metabolic reprogramming that includes an increase in glucose uptake and glycolysis, alterations in NAD(P)H/NAD(P)+ and intracellular ATP levels, and increased utilization of glutamine as the major precursor for fatty acid synthesis. In this chapter, we describe in detail various physiological assays that have been adopted to study the metabolic shift propagated by exposure to hypoxic conditions in pancreatic cell culture model that includes glucose uptake, glutamine uptake, and lactate release by pancreatic cancer cell lines...
2018: Methods in Molecular Biology
Sui Seng Tee, Izabela Suster, Steven Truong, Sangmoo Jeong, Roozbeh Eskandari, Valentina DiGialleonardo, Julio A Alvarez, Hannah N Aldeborgh, Kayvan R Keshari
The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials, and this study investigates the effect of MK2206, a non-ATP-competitive inhibitor, on the cellular metabolism of prostate cancer cells. We observed a reduction in cell motility and aerobic glycolysis in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes and transporters involved in glycolysis...
March 2018: Molecular Cancer Research: MCR
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