17 results on '"Brenner, Charles"'
Search Results
2. Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans
- Author
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Bieganowski, Pawel and Brenner, Charles
- Subjects
- *
NICOTINAMIDE , *GENES , *FUNGI , *COENZYMES - Abstract
NAD+ is essential for life in all organisms, both as a coenzyme for oxidoreductases and as a source of ADPribosyl groups used in various reactions, including those that retard aging in experimental systems. Nicotinic acid and nicotinamide were defined as the vitamin precursors of NAD+ in Elvehjem''s classic discoveries of the 1930s. The accepted view of eukaryotic NAD+ biosynthesis, that all anabolism flows through nicotinic acid mononucleotide, was challenged experimentally and revealed that nicotinamide riboside is an unanticipated NAD+ precursor in yeast. Nicotinamide riboside kinases from yeast and humans essential for this pathway were identified and found to be highly specific for phosphorylation of nicotinamide riboside and the cancer drug tiazofurin. Nicotinamide riboside was discovered as a nutrient in milk, suggesting that nicotinamide riboside is a useful compound for elevation of NAD+ levels in humans. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
3. Evolutionary Fate of an Unstable Human Minisatellite Deduced from Sperm-Mutation Spectra of Individual Alleles.
- Author
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Buard, J é r ô me, Brenner, Charles, and Jeffreys, Alec J.
- Subjects
- *
MICROSATELLITE repeats , *SPERMATOZOA , *GENETIC mutation - Abstract
Although mutation processes at some human minisatellites have been extensively characterized, the evolutionary fate of these unstable loci is unknown. Minisatellite instability is largely germline specific, with mutation rates up to several percent and with expansion events predominating over contractions. Using allele-specific small-pool polymerase chain reaction, we have determined sperm-mutation spectra of individual alleles of the highly unstable human minisatellite CEB1 (i.e., D2S90). We show that, as allele size increases, the proportion of contractions rises from !5% to 50%, with the average size of deletion increasing and eventually exceeding the average size of expansion. The expected net effect of these trends after many generations is an equilibrium distribution of allele sizes, and allele-frequency data suggest that this equilibrium state has been reached in some contemporary human populations. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
4. NAD as a Genotype-Specific Drug Target.
- Author
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Mei, Szu-Chieh and Brenner, Charles
- Subjects
- *
DRUG target , *HIGH throughput screening (Drug development) , *GENETIC testing , *NAD (Coenzyme) , *PHOSPHORIBOSYLTRANSFERASES , *NICOTINAMIDE - Abstract
Using high-throughput chemical and genetic screening, Matheny and colleagues (in this issue of Chemistry & Biology) identified STF-118804, an inhibitor of nicotinamide phosphoribosyltransferase, as a cell type-specific inhibitor of mixed-lineage leukemia with MLL chromosomal rearrangements. The approach was powerful, as is the potential for NAD as a specific cancer target. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
5. Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk and Urh1/Pnp1/Meu1 Pathways to NAD+
- Author
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Belenky, Peter, Racette, Frances G., Bogan, Katrina L., McClure, Julie M., Smith, Jeffrey S., and Brenner, Charles
- Subjects
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NIACIN , *BIOSYNTHESIS , *AMIDES , *BIOCHEMISTRY - Abstract
Summary: Although NAD+ biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD+ precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD+ precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD+ synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD+ metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD+ and increases Sir2 function. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
6. Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast
- Author
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Parsons, Ainslie B., Lopez, Andres, Givoni, Inmar E., Williams, David E., Gray, Christopher A., Porter, Justin, Chua, Gordon, Sopko, Richelle, Brost, Renee L., Ho, Cheuk-Hei, Wang, Jiyi, Ketela, Troy, Brenner, Charles, Brill, Julie A., Fernandez, G. Esteban, Lorenz, Todd C., Payne, Gregory S., Ishihara, Satoru, Ohya, Yoshikazu, and Andrews, Brenda
- Subjects
- *
BIOACTIVE compounds , *BIOCHEMICAL genetics , *TAMOXIFEN , *PHOSPHATIDYLSERINES - Abstract
Summary: Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of “chemical-genetic interaction” profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular pathways and proteins affected, we applied both a hierarchical clustering and a factorgram method, which allows a gene or compound to be associated with more than one group. In particular, tamoxifen, a breast cancer therapeutic, was found to disrupt calcium homeostasis and phosphatidylserine (PS) was recognized as a target for papuamide B, a cytotoxic lipopeptide with anti-HIV activity. Further, the profile of crude extracts resembled that of its constituent purified natural product, enabling detailed classification of extract activity prior to purification. This compendium should serve as a valuable key for interpreting cellular effects of novel compounds with similar activities. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
7. NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging.
- Author
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Levine, Daniel C., Hong, Heekyung, Weidemann, Benjamin J., Ramsey, Kathryn M., Affinati, Alison H., Schmidt, Mark S., Cedernaes, Jonathan, Omura, Chiaki, Braun, Rosemary, Lee, Choogon, Brenner, Charles, Peek, Clara Bien, and Bass, Joseph
- Subjects
- *
MOLECULAR clock , *NUCLEAR counters , *POST-translational modification , *AGING , *METABOLIC regulation , *HEAT shock factors , *OLD age - Abstract
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock. • NAD+ induces transcription of stress and metabolic genes through the circadian clock • BMAL1 is required for chromatin remodeling and HSF1 recruitment in response to NAD+ • NAD+ regulates PER2 acetylation and localization to control feedback repression • NAD+ counters age-related decline in circadian function Aging is associated with disrupted circadian rhythms through signals that remain unidentified. Levine et al. show that NAD+ controls global circadian transcription through post-translational modification of PER2 and feedback repression. Raising NAD+ restores youthful transcription and mitochondrial rhythms in old age, revealing that NAD+ governs both behavior and metabolic health. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
8. Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging.
- Author
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Sato, Shogo, Solanas, Guiomar, Peixoto, Francisca Oliveira, Bee, Leonardo, Symeonidi, Aikaterini, Schmidt, Mark S., Brenner, Charles, Masri, Selma, Benitah, Salvador Aznar, and Sassone-Corsi, Paolo
- Subjects
- *
AGING , *CIRCADIAN rhythms , *HOMEOSTASIS , *LOW-calorie diet , *GENE expression - Abstract
Summary The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD + -related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
9. Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy.
- Author
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Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Ulla Heinonen JK, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, and Suomalainen A
- Published
- 2020
- Full Text
- View/download PDF
10. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.
- Author
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Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N, Wilson M, Lucas SJE, Akerman I, Seabright A, Lai YC, Tennant DA, Nightingale P, Wallis GA, Manolopoulos KN, Brenner C, Philp A, and Lavery GG
- Subjects
- Aged, Aged, 80 and over, Aging drug effects, Cross-Sectional Studies, Cytokines drug effects, Double-Blind Method, Humans, Male, Muscle, Skeletal drug effects, NAD metabolism, Niacinamide pharmacology, Pyridinium Compounds, Aging metabolism, Anti-Inflammatory Agents blood, Cytokines blood, Metabolome drug effects, Muscle, Skeletal metabolism, Niacinamide analogs & derivatives, Transcriptome drug effects
- Abstract
Nicotinamide adenine dinucleotide (NAD
+ ) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
11. Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring.
- Author
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Ear PH, Chadda A, Gumusoglu SB, Schmidt MS, Vogeler S, Malicoat J, Kadel J, Moore MM, Migaud ME, Stevens HE, and Brenner C
- Subjects
- Animals, Female, Lactation drug effects, Lactation metabolism, Liver metabolism, Liver pathology, Mice, NAD metabolism, Niacinamide adverse effects, Niacinamide pharmacology, Pregnancy, Prenatal Exposure Delayed Effects chemically induced, Prenatal Exposure Delayed Effects pathology, Pyridinium Compounds, Maternal Exposure adverse effects, Neurogenesis drug effects, Niacinamide analogs & derivatives, Postpartum Period metabolism, Prenatal Exposure Delayed Effects metabolism, Weight Loss drug effects
- Abstract
Conditions of metabolic stress dysregulate the NAD metabolome. By restoring NAD, nicotinamide riboside (NR) provides resistance to such conditions. We tested the hypotheses that postpartum might dysregulate maternal NAD and that increasing systemic NAD with NR might benefit mothers and offspring. In postpartum mothers, the liver NAD metabolome is depressed while blood increases circulation of NAD metabolites to enable a >20-fold increase in mammary NAD
+ and NADP+ . Lactation and NR synergize in stimulating prolactin synthesis and mammary biosynthetic programs. NR supplementation of new mothers increases lactation and nursing behaviors and stimulates maternal transmission of macronutrients, micronutrients, and BDNF into milk. Pups of NR-supplemented mothers are advantaged in glycemic control, size at weaning, and synaptic pruning. Adult offspring of mothers supplemented during nursing retain advantages in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis. Thus, postgestational maternal micronutrition confers lasting advantages to offspring., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
12. Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.
- Author
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Mitchell SJ, Bernier M, Aon MA, Cortassa S, Kim EY, Fang EF, Palacios HH, Ali A, Navas-Enamorado I, Di Francesco A, Kaiser TA, Waltz TB, Zhang N, Ellis JL, Elliott PJ, Frederick DW, Bohr VA, Schmidt MS, Brenner C, Sinclair DA, Sauve AA, Baur JA, and de Cabo R
- Subjects
- Animals, Diet, High-Fat, Disease Models, Animal, Fatty Liver drug therapy, Inflammation drug therapy, Longevity, Mice, Inbred C57BL, Niacinamide administration & dosage, Oxidative Stress drug effects, Sirtuin 1 metabolism, Dietary Supplements, Healthy Aging metabolism, Liver drug effects, Liver metabolism, NAD metabolism, Niacinamide pharmacology
- Abstract
The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD
+ , is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Targeted NAD metabolome analysis in liver revealed depressed expression of NAM salvage in NAM-treated mice, an effect counteracted by higher expression of de novo NAD biosynthetic enzymes. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects., (Published by Elsevier Inc.)- Published
- 2018
- Full Text
- View/download PDF
13. NNMT: A Bad Actor in Fat Makes Good in Liver.
- Author
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Trammell SA and Brenner C
- Subjects
- Animals, Female, Humans, Male, Liver metabolism, Nicotinamide N-Methyltransferase physiology, Sirtuin 1 physiology
- Abstract
High adipose expression of NNMT, an enzyme that converts nicotinamide to 1-methyl-nicotinamide, correlates with adiposity. Though murine NNMT knockdown in fat and liver prevents weight gain on high-fat diet, Hong et al. (2015) now show that high hepatic expression of NNMT improves lipid parameters via SIRT1 stabilization., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
14. Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation.
- Author
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Wu BK and Brenner C
- Subjects
- Animals, Cell Proliferation, Gene Expression, Gene Expression Regulation, Neoplastic, Genomic Imprinting, Humans, MAP Kinase Signaling System, Mice, Mixed Function Oxygenases, NIH 3T3 Cells, Proto-Oncogene Proteins p21(ras), Cell Transformation, Neoplastic genetics, DNA Methylation, DNA-Binding Proteins physiology, Proto-Oncogene Proteins physiology, ras Proteins physiology
- Abstract
Hypermethylation-mediated tumor suppressor gene (TSG) silencing is a central epigenetic alteration in RAS-dependent tumorigenesis. Ten-eleven translocation (TET) enzymes can depress DNA methylation by hydroxylation of 5-methylcytosine (5mC) bases to 5-hydroxymethylcytosine (5hmC). Here, we report that suppression of TET1 is required for KRAS-induced DNA hypermethylation and cellular transformation. In distinct nonmalignant cell lines, oncogenic KRAS promotes transformation by inhibiting TET1 expression via the ERK-signaling pathway. This reduces chromatin occupancy of TET1 at TSG promoters, lowers levels of 5hmC, and increases levels of 5mC and 5mC-dependent transcriptional silencing. Restoration of TET1 expression by ERK pathway inhibition or ectopic TET1 reintroduction in KRAS-transformed cells reactivates TSGs and inhibits colony formation. KRAS knockdown increases TET1 expression and diminishes colony-forming ability, whereas KRAS/TET1 double knockdown bypasses the KRAS dependence of KRAS-addicted cancer cells. Thus, suppression of TET1-dependent DNA demethylation is critical for KRAS-mediated transformation., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
15. Boosting NAD to spare hearing.
- Author
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Brenner C
- Subjects
- Animals, Female, Male, Hearing Loss, Noise-Induced prevention & control, NAD therapeutic use, Niacinamide analogs & derivatives, Sirtuin 3 metabolism
- Abstract
Ex vivo experiments have strangely shown that inhibition or stimulation of NAD metabolism can be neuroprotective. In this issue of Cell Metabolism, Brown et al. (2014) demonstrate that cochlear NAD is diminished by deafening noise but protected by nicotinamide riboside or WldS mutation. Hearing protection by nicotinamide riboside depends on Sirt3., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
16. Evolution of NAD biosynthetic enzymes.
- Author
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Brenner C
- Subjects
- Protein Conformation, Evolution, Molecular, NAD biosynthesis, Pentosyltransferases chemistry, Pentosyltransferases genetics
- Abstract
Two research groups have solved crystal structures of nicotinic acid phosphoribosyltransferase (PRTase) and made the argument that PRTases in three distinct pathways of nicotinamide adenine dinucleotide (NAD) biosynthesis evolved from a common ancestor (Shin et al., 2005 and Chappie et al., 2005).
- Published
- 2005
- Full Text
- View/download PDF
17. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.
- Author
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Bieganowski P and Brenner C
- Subjects
- Chromosomes, Human, Pair 9 genetics, Energy Metabolism genetics, Evolution, Molecular, Fungi genetics, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Fungal genetics, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Niacinamide chemistry, Nucleosides chemistry, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor) isolation & purification, Pyridinium Compounds, Ribavirin chemistry, Ribavirin pharmacology, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins isolation & purification, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Fungi enzymology, NAD biosynthesis, Niacinamide analogs & derivatives, Niacinamide metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Ribavirin analogs & derivatives, Saccharomyces cerevisiae Proteins metabolism
- Abstract
NAD+ is essential for life in all organisms, both as a coenzyme for oxidoreductases and as a source of ADPribosyl groups used in various reactions, including those that retard aging in experimental systems. Nicotinic acid and nicotinamide were defined as the vitamin precursors of NAD+ in Elvehjem's classic discoveries of the 1930s. The accepted view of eukaryotic NAD+ biosynthesis, that all anabolism flows through nicotinic acid mononucleotide, was challenged experimentally and revealed that nicotinamide riboside is an unanticipated NAD+ precursor in yeast. Nicotinamide riboside kinases from yeast and humans essential for this pathway were identified and found to be highly specific for phosphorylation of nicotinamide riboside and the cancer drug tiazofurin. Nicotinamide riboside was discovered as a nutrient in milk, suggesting that nicotinamide riboside is a useful compound for elevation of NAD+ levels in humans.
- Published
- 2004
- Full Text
- View/download PDF
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