99 results on '"Brenner, Charles"'
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2. Learning biology to understand longevity.
- Author
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Brenner, Charles
- Subjects
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LONGEVITY , *BIOLOGY , *SOMATOTROPIN receptors , *MOLECULAR biology - Published
- 2024
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3. Emerging potential benefits of modulating NAD+ metabolism in cardiovascular disease.
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Matasic, Daniel S., Brenner, Charles, and London, Barry
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CARDIOVASCULAR diseases , *MITOCHONDRIA - Abstract
Nicotinamide adenine dinucleotide (and+) NAD related metabolites are central mediators of fuel oxidation and bioenergetics within cardiomyocytes. Additionally, NAD+ is required for the activity of multifunctional enzymes, including sirtuins and poly(ADP-ribose) polymerases that regulate posttranslational modifications, DNA damage responses, and Ca2+ signaling. Recent research has indicated that NAD+ participates in a multitude of processes dysregulated in cardiovascular diseases. Therefore, supplementation of NAD+ precursors, including nicotinamide riboside that boosts or repletes the NAD+ metabolome, may be cardioprotective. This review examines the molecular physiology and preclinical data with respect to NAD+ precursors in heart failure-related cardiac remodeling, ischemic-reperfusion injury, and arrhythmias. In addition, alternative NAD+-boosting strategies and potential systemic effects of NAD+ supplementation with implications on cardiovascular health and disease are surveyed. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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4. A science-based review of the world's best-selling book on aging.
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Brenner, Charles
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ACTIVE aging , *LONGEVITY - Abstract
• Members of the general public and investment community have caught the longevity bug and appear to believe that major breakthroughs have been made in extending human lifespan. • Lifespan , a book by Harvard scientist David Sinclair, has become an influential source of misinformation on longevity, featuring counterfactual claims about longevity genes being conserved between yeast and humans, the existence of supposed activators of these genes, and claimed successful age reversal in mice based on partial reprogramming. • The book has popularized a stack of drugs and supplements with significant potential to harm the general public. • The reviewer suggests that scientists and physicians emphasize to the general public that aging is known to be a highly polygenic developmental process and that the most important things that people can do to age better are to maintain high physical and mental activity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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5. Calorie Restriction-Mediated Replicative Lifespan Extension in Yeast Is Non-Cell Autonomous.
- Author
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Mei, Szu-Chieh and Brenner, Charles
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YEAST research , *LIFE spans , *LOW-calorie diet , *CELL communication , *STEM cells , *MULTICELLULAR organisms , *DEVELOPMENTAL biology - Abstract
Calorie-restriction extends lifespan in many multicellular organisms; here substances secreted by calorie-restricted yeast are found to induce longer life in other yeast cells, suggesting that cellular communication is a component of this phenomenon even in a single-celled organism. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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6. A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1.
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Boylston, Jennifer A. and Brenner, Charles
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- 2014
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7. Quantification of Protein Copy Number in Yeast: The NAD+ Metabolome.
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Mei, Szu-Chieh and Brenner, Charles
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DNA copy number variations , *YEAST fungi genetics , *SACCHAROMYCES cerevisiae , *ALDEHYDE dehydrogenase , *METABOLOMICS , *MOLECULAR biology - Abstract
Saccharomyces cerevisiae is calorie-restricted by lowering glucose from 2% to 0.5%. Under low glucose conditions, replicative lifespan is extended in a manner that depends on the NAD+-dependent protein lysine deacetylase Sir2 and NAD+ salvage enzymes. Because NAD+ is required for glucose utilization and Sir2 function, it was postulated that glucose levels alter the levels of NAD+ metabolites that tune Sir2 function. Though NAD+ precursor vitamins, which increase the levels of all NAD+ metabolites, can extend yeast replicative lifespan, glucose restriction does not significantly change the levels or ratios of intracellular NAD+ metabolites. To test whether glucose restriction affects protein copy numbers, we developed a technology that combines the measurement of Urh1 specific activity and quantification of relative expression between Urh1 and any other protein. The technology was applied to obtain the protein copy numbers of enzymes involved in NAD+ metabolism in rich and synthetic yeast media. Our data indicated that Sir2 and Pnc1, two enzymes that sequentially convert NAD+ to nicotinamide and then to nicotinic acid, are up-regulated by glucose restriction in rich media, and that Pnc1 alone is up-regulated in synthetic media while levels of all other enzymes are unchanged. These data suggest that production or export of nicotinic acid might be a connection between NAD+ and calorie restriction-mediated lifespan extension in yeast. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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8. Rethinking Premedical and Health Professional Curricula in Light of MCAT 2015.
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Brenner, Charles
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CURRICULUM , *UNIVERSITY & college admission , *MEDICAL school admission , *BIOCHEMISTRY education , *VOCATIONAL guidance - Abstract
The 2015 redesign of the Medical College Admissions Test (MCAT) is a disruptive event that has stimulated a great deal of discussion in undergraduate educational circles. These discussions include figuring out who will teach biochemistry, whether nonmajor chemistry courses should be changed, whether the psychosocial material to be tested constitutes academic behavioral science or the sensibilities that come from exposure to different cultures, and determining whether resources need to shift. The 2015 MCAT has also begun to alter admissions requirements and curricula in medical, pharmacy, and dental schools. Though many medical schools are taking the position that biochemistry will already have been covered as an undergraduate requirement and seem to be deemphasizing molecular science in the first-year curriculum, at least one college of dentistry has embraced the better prepared first-year student in order to offer advanced biochemistry and genomics that will build on undergraduate biochemistry. [ABSTRACT FROM AUTHOR]
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- 2013
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9. A Western Eurasian Male Is Found in 2000-Year-Old Elite Xiongnu Cemetery in Northeast Mongolia.
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Kijeong Kim, Brenner, Charles H., Mair, Victor H., Kwang-Ho Lee, Jae-Hyun Kim, Gelegdorj, Eregzen, Batbold, Natsag, Yi-Chung Song, Hyeung-Won Yun, Eun-Jeong Chang, Lkhagvasuren, Gavaachimed, Bazarragchaa, Munkhtsetseg, Park, Ae-Ja, Lim, Inja, Yun-Pyo Hong, Wonyong Kim, Sang-In Chung, Dae-Jin Kim, Yoon-Hee Chung, and Sung-Su Kim
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EURASIANS , *GENETIC polymorphisms , *NUCLEOTIDE sequence , *DNA , *GENETIC markers , *SOCIAL stratification - Abstract
We analyzed mitochondrial DNA (mtDNA), Y-chromosome single nucleotide polymorphisms (Y-SNP), and autosomal short tandem repeats (STR) of three skeletons found in a 2,000-year-old Xiongnu elite cemetery in Duurlig Nars of Northeast Mongolia. This study is one of the first reports of the detailed genetic analysis of ancient human remains using the three types of genetic markers. The DNA analyses revealed that one subject was an ancient male skeleton with maternal U2e1 and paternal R1a1 haplogroups. This is the first genetic evidence that a male of distinctive Indo-European lineages (R1a1) was present in the Xiongnu of Mongolia. This might indicate an Indo-European migration into Northeast Asia 2,000 years ago. Other specimens are a female with mtDNA haplogroup D4 and a male with Y-SNP haplogroup C3 and mtDNA haplogroup D4. Those haplogroups are common in Northeast Asia. There was no close kinship among them. The genetic evidence of U2e1 and R1a1 may help to clarify the migration patterns of Indo-Europeans and ancient East-West contacts of the Xiongnu Empire. Artifacts in the tombs suggested that the Xiongnu had a system of the social stratification. The West Eurasian male might show the racial tolerance of the Xiongnu Empire and some insight into the Xiongnu society. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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10. 5′-Nucleotidases and their new roles in NAD+and phosphate metabolismThis article is part of a themed issue on Biophosphates, and is dedicated to Professor Wojciech J. Stec on the occasion of his 70th birthday.
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Bogan, Katrina L. and Brenner, Charles
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HYDROLASES , *NAD (Coenzyme) , *PHOSPHATES , *HYDROLYSIS , *NUCLEOSIDES , *EXTRACELLULAR enzymes , *PURINERGIC receptors , *DNA replication - Abstract
5′-Nucleotidase (EC 3.1.3.5) designates a set of enzymes, which catalyze the hydrolysis of ribonucleoside and deoxyribonucleoside monophosphates into the corresponding nucleosides plus orthophosphate. 5′-Nucleotidases are classified according to subcellular localization, nucleobase specificity and their ability to hydrolyze deoxynucleoside monophosphate substrates. Membrane-bound 5′-nucleotidases are ectoenzymes principally involved in salvage of extracellular nucleosides, and often display a preference toward adenosine monophosphate, thereby modulating signal transduction cascades involving purinergic receptors. Cytosolic 5′-nucleotidases are members of the haloacid dehalogenase superfamily of enzymes, which are two-domain proteins containing a modified Rossman fold as the core and a variable cap structure. Extracellular and intracellular 5′-nucleotidase activities participate in purine and pyrimidine salvage to support balanced synthesis of nucleotides, which is critical for maintaining high fidelity DNA replication. While the production of ribonucleosides from ribonucleotides by 5′-nucleotidases remains the most well studied function, it appears that the physiological functions of these activities are more broad. Indeed, Sdt1, previously termed a pyrimidine-specific 5′-nucleotidase, and Isn1, previously termed an inosine monophosphate (IMP)-specific 5′-nucleotidase, have recently been implicated in catabolic processes in nicotinamide adenine dinucleotide (NAD+) metabolism, and are regulated by the NAD+precursor vitamin nicotinic acid, glucose and phosphate availability in the medium. In addition, Usha, Pho5, Sdt1 and Phm8 are phosphate starvation-induced 5′-nucleotidases with diverse substrate specificities that liberate phosphate under phosphate starvation conditions. Here we review 5′-nucleotidase enzyme structure, catalytic mechanism and substrate specificity and focus on new biological roles for these enzymes in nucleotide, NAD+and phosphate metabolism. [ABSTRACT FROM AUTHOR]
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- 2010
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11. Nicotinic Acid, Nicotinamide, and Nicotinainide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition.
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Bogan, Katrina L. and Brenner, Charles
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NICOTINAMIDE , *NIACIN , *AMIDES , *NUTRITION , *VITAMINS , *NEURODEGENERATION , *BIOSYNTHESIS - Abstract
Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-Specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports nenronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research. [ABSTRACT FROM AUTHOR]
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- 2008
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12. Some mathematical problems in the DNA identification of victims in the 2004 tsunami and similar mass fatalities
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Brenner, Charles H.
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DNA fingerprinting , *EARTH sciences , *IDENTIFICATION , *FORENSIC sciences - Abstract
Abstract: DNA is a major and essential identification tool for mass fatality incidents including the hundreds of thousands of victims of the 2004 Indian Ocean tsunami. Mathematical complications characteristic of this sort of mass fatality include prevalence of related victims, the many races represented among the victims, and various identification modalities in tandem with DNA. Four mathematical problems of interest are discussed in this paper. (1) Other quantifiable factors (i.e. geography) can be formally accounted for by including a likelihood ratio that can be thought of as reducing the “effective number of victims.” (2) When a victim is found and tentatively identified as V, but then it comes to light that the victim has a relative W who is also missing, confidence in the identity is depressed. To account for the existence of W, increment the effective number of victims by the likelihood ratio supporting W as the identity of the victim. (3) When several apparently related victims are found, their mutual identities should be calculated simultaneously. Compared to one-at-a-time, serial identifications, this is both logical and may lead to much more confidence in the identities. (4) Although there may be many different population groups represented among the missing, it is generally sufficient to consider population statistics for only a few of them in deciding whether to declare an identification. [Copyright &y& Elsevier]
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- 2006
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13. Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans
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Bieganowski, Pawel and Brenner, Charles
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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
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14. The Reported Human NADsyn2 Is Ammonia-dependent NAD Synthetase from a Pseudomonad.
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Bieganowski, Pawel and Brenner, Charles
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NAD (Coenzyme) , *LIGASES , *AMMONIA , *PSEUDOMONAS - Abstract
Nicotinamide-adenine dinucleotide (NAD[sup +]) synthetases catalyze the last step in NAD[sup +] metabolism in the de novo, import, and salvage pathways that originate from tryptophan (or aspartic acid), nicotinic acid, and nicotinamide, respectively, and converge on nicotinic acid mononucleotide. NAD[sup +] synthetase converts nicotinic acid adenine dinucleotide to NAD[sup +] via an adenylylated intermediate. All of the known eukaryotic NAD[sup +] synthetases are glutamine-dependent, hydrolyzing glutamine to glutamic acid to provide the attacking ammonia. In the prokaryotic world, some NAD[sup +] synthetases are glutamine-dependent, whereas others can only use ammonia. Earlier, we noted a perfect correlation between presence of a domain related to nitrilase and glutamine dependence and then proved in the accompanying paper (Bieganowski, P., Pace, H. C., and Brenner, C. (2003) J. Biol. Chem. 278, 33049-33055) that the nitrilase-related domain is an essential, obligate intramolecular, thiol-dependent glutamine amidotransferase in the yeast NAD[sup +] synthetase, Qns1. Independently, human NAD[sup +] synthetase was cloned and shown to depend on Cys-175 for glutamine-dependent but not ammoniadependent NAD[sup +] synthetase activity. Additionally, it was claimed that a 275 amino acid open reading frame putatively amplified from human glioma cell line LN229 encodes a human ammonia-dependent NAD[sup +] synthetase and this was speculated largely to mediate NAD[sup +] synthesis in human muscle tissues. Here we establish that the so-called NADsyn2 is simply ammonia-dependent NAD[sup +] synthetase from Pseudomonas, which is encoded on an operon with nicotinic acid phosphorlbosyltransferase and, in some Pseudomonads, with nicotinamidase. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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15. Catalysis in the nitrilase superfamily
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Brenner, Charles
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CATALYSIS , *NITRILES - Abstract
Recently, we defined the nitrilase superfamily as consisting of 12 families of amidases, N-acyltransferases and presumptive amidases, in addition to the family of plant and bacterial nitrilases for which the superfamily was named. A novel Glu-Lys-Cys catalytic triad, found at the crystallographically defined Nit active site of worm NitFhit, was postulated to constitute the catalytic residues for all members of the superfamily. Recent experimental results confirm the essentiality of the catalytic triad residues and specify the biochemical functions of additional branches and sub-branches of the nitrilase superfamily. [Copyright &y& Elsevier]
- Published
- 2002
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16. Hint, Fhit, and GalT: Function, Structure, Evolution, and Mechanism of Three Branches of the Histidine Triad Superfamily of Nucleotide Hydrolases and Transferases.
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Brenner, Charles
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NUCLEOTIDES , *ADENOSINES - Abstract
Examines the enzyme mechanism of three branches of histidine triad superfamily of nucleotide hydrolases and transferases. Presence of adenosine monophosphoramide hydrolases in the Hint branch; Mutation of aprataxin in ataxia-oculomotor apraxia syndrome; Biological activities of histidine proteins.
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- 2002
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17. Evolutionary Fate of an Unstable Human Minisatellite Deduced from Sperm-Mutation Spectra of Individual Alleles.
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Buard, J é r ô me, Brenner, Charles, and Jeffreys, Alec J.
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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]
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- 2002
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18. The Neonate and Mentation.
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Brenner, Charles
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PATHOLOGICAL psychology , *MIND & body , *DEATH instinct , *PSYCHOANALYSIS - Abstract
Explores the principal points underlying an article about psychopathology. Questions raised by the article that psychopathology is a struggle between Eros and Thanatos; Fundamental motives for thought and behavior; Purpose of psychoanalysis.
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- 2000
19. TECHNICAL COMMENT ABSTRACTS.
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Brenner, Charles, Klein, Samuel, and Yoshino, Mihoko
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NICOTINAMIDE , *INSULIN sensitivity - Published
- 2021
20. Quantitative assessment of enzyme specificity in vivo: P2 recognition by Kex2 protease defined in...
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Bevan, Alison, Brenner, Charles, and Fuller, Robert S.
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PROTEOLYTIC enzymes , *GENES - Abstract
Highlights a study which used a sensitive, quantitative assay to analyze the yeast proprotein-processing Kex2 protease's specificity. Development of a prepro-alpha-factor gene; Expression of the wild-type and mutant precursors; Methodology used to conduct the study; Results of the study.
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- 1998
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21. Arg21 is the preferred kexin cleavage site in parathyroid-hormone-related protein.
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Diefenbach-Jagger, Hanne, Brenner, Charles, Kemp, Bruce E., Baron, Will, McLean, John, Martin, T. John, and Moseley, Jane M.
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PARATHYROID hormone-related protein , *PROTEOLYTIC enzymes , *ALANINE , *ARGININE , *PEPTIDES , *PARACRINE mechanisms - Abstract
Parathyroid-hormone-related protein (PTHrP) contains several potential sites for proteolytic processing. Although there is considerable evidence for the existence of cleaved products in vivo, little is known about the post-translational processing of PTHrP. We have used purified kexin (Kex2) protease to identify which cleavage sites in recombinant PTHrP(1-141) might be of physiological significance. Cleavage products were identified by N-terminal sequencing. Kex2 preferentially cleaved PTHrP(1-141) carboxy to the triplet aminine site Apg-Arg-Arg2t with a Km of 3.3 ± 1.7 µM and a kcat of 6 ± 1.2 s-1. Substitution of alanine for Arg19 resulted in substantially reduced conversion, while no detectable cleavage occurred when alanine was substituted for either Arg20 or Arg21. In contrast, the degree of Kex2 cleavage at Arg21 in PTHrP(1-34) was lower. No detectable cleavage occurred in an unrelated synthetic peptide containing both double and triple arginine sites. Low levels of cleavage also took place carboxy to Lys-Arg97, LysArg105, Arg-Arg106 and Thr-Arg108. Cleavage carboxy to Lys-Arg105, the best of these minor sites, occurred with a Km of 8.4 ± 2.7 µM and a kcat of 0.8 ± 0.2 s-1. These studies indicate that the preferred Kex2 cleavage site in PTHrP(1-141) is carboxy to Arg-Arg-Arg21, which effectively destroys its parathyroidhormone-like biological activity. Cleavage of this site by Kex2-related mammalian convertases in vivo may be an important mechanism for full elaboration of the non-parathyroid-hormone-like paracrine actions of PTHrP in a tissue-specific manner. [ABSTRACT FROM AUTHOR]
- Published
- 1995
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22. Why Is Mom Stressed: Homeorhesis as the Potential Problem and Nicotinamide Riboside as the Potential Solution.
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Brenner, Charles
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NICOTINAMIDE , *BRAIN-derived neurotrophic factor , *BODY composition , *POSTPARTUM depression , *NUTRITION - Abstract
The remodeling of female mammalian physiology to support the development of a fertilized egg into an externally breathing individual and then to provide all the nutrition to this individual while remodeling back to nearly her pregestational state is without parallel in male mammalian physiological transitions. While it is common parlance to refer to postpartum depression as a not infrequent stress in women, the postpartum physiological changes after every birth constitute profound metabolic stresses that are understudied and have important nutritional, behavioral, and neurodevelopmental implications for the maternal and neonatal health of every mammalian species. We discovered that the postpartum liver of a lactating female mouse has a depressed nicotinamide adenine dinucleotide (NAD) metabolome linked to circulation of higher levels of NAD metabolites in support of a >20-fold increase in NAD coenzymes in the mammary. Furthermore, by supporting a new mother's apparent higher demand for NAD precursors, we increased circulation of prolactin, superinduced mammary biosynthetic programs, increased her time of arched-back nursing, enhanced mammary production of brain-derived neurotrophic factor, promoted postgestational weight loss, advanced the neurobehavioral development of her offspring, and allowed them to mature as stronger and more resilient adults with advantages in hippocampal neurogenesis and body composition. These results show that a new mother's capacity for biosynthesis and functionally important nurturing is apparently limited by NAD. Here, we discuss homeorhetic flow of resources from a new mother to her offspring in the context of NAD metabolism and suggest avenues for future investigation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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23. Herod the Great Remains True to Form.
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Brenner, Charles
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COINS , *KINGS & rulers - Abstract
Focuses on the coins belonging to the rule of King Herod of Judaea. Presence of the picture of a Greekor Roman helmet on Herod's coins; Theme of Discuri caps on the coins; Depiction of a Greek deity on the coins.
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- 2001
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24. NAD in pathological cardiac remodeling: Metabolic regulation and beyond.
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Norambuena-Soto, Ignacio, Deng, Yingfeng, Brenner, Charles, Lavandero, Sergio, and Wang, Zhao V.
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METABOLIC regulation , *HEART metabolism disorders , *HEART diseases , *COENZYMES , *HEART failure , *MYOCARDIAL reperfusion , *MITOCHONDRIA - Abstract
Nicotinamide adenine dinucleotide (NAD) coenzymes are carriers of high energy electrons in metabolism and also play critical roles in numerous signaling pathways. NAD metabolism is decreased in various cardiovascular diseases. Importantly, stimulation of NAD biosynthesis protects against heart disease under different pathological conditions. In this review, we describe pathways for both generation and catabolism of NAD coenzymes and the respective changes of these pathways in the heart under cardiac diseases, including pressure overload, myocardial infarction, cardiometabolic disease, cancer treatment cardiotoxicity, and heart failure. We next provide an update on the strategies and treatments to increase NAD levels, such as supplementation of NAD precursors, in the heart that prevent or reverse cardiomyopathy. We also introduce the approaches to manipulate NAD consumption enzymes to ameliorate cardiac disease. Finally, we discuss the mechanisms associated with improvements in cardiac function by NAD coenzymes, differentiating between mitochondria-dependent effects and those independent of mitochondrial metabolism. • NAD coenzymes are decreased in the heart under various cardiovascular diseases. • Elevation of the availability of NAD coenzymes improves cardiac function and ameliorates cardiomyopathy. • Molecular mechanisms of NAD cardioprotection may involve mitochondria-dependent and -independent actions. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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25. Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
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Zhang, Quanjiang, Li, Zhonggang, Li, Qiuxia, Trammell, Samuel AJ, Schmidt, Mark S, Pires, Karla Maria, Cai, Jinjin, Zhang, Yuan, Kenny, Helena, Boudina, Sihem, Brenner, Charles, and Abel, E Dale
- Subjects
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NAD (Coenzyme) , *MITOCHONDRIA , *HOMEOSTASIS , *HEART diseases , *HEART failure , *NICOTINAMIDE - Abstract
Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+. Synopsis: How autophagy safeguards cardiac structure and function to prevent heart failure remains unclear. This genetic work links a novel connection between deficient autophagic flux in cardiomyocytes to reduced availability of the cellular metabolite NAD+, suggesting novel tractable avenues for intervention. Depletion of autophagy-related protein 3 (ATG3) in cardiomyocytes causes cardiac dysfunction and early mortality in mice. ATG3 depletion reduces mitochondrial metabolism and biogenesis, preceding age-dependent cardiac dysfunction. Reduced autophagy leads to accumulation of SQSTM1, activation of NF-κB subunit RELA, and increased transcription of the NAD+ metabolic enzyme NNMT. Increased NNMT catalyzes the competing conversion of NAD+ precursor NAM to MeNAM, leading to NAD+ deficiency. Autophagy induction prevents NNMT induction and NNMT inhibition or NMN supplementation restore cardiac and mitochondrial dysfunction when autophagy is defective. Deficient autophagy reduces NAD+ availability in cardiomyocytes via a SQSTM1-NF-κB-NNMT axis, contributing to mitochondrial dysfunction and heart failure. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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26. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults.
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Conze, Dietrich, Brenner, Charles, and Kruger, Claire L.
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- 2019
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27. Longevity lessons.
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Brenner, Charles
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AGING , *NONFICTION - Published
- 2022
28. Metabolism: Targeting a fat-accumulation gene.
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Brenner, Charles
- Subjects
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FAT cells , *ENZYMES , *LABORATORY mice , *DIABETES , *OBESITY - Abstract
The article focuses on a enzyme that links two metabolic hubs in human body. It states that the enzyme has been found to be unregulated in the fat cells of overweight mice. It further states that the inhibition of the gene encoding this enzyme protects mice from diet-induced obesity. It further highlights that mice that lack or overexpress GLUT4 in fat are used as models for people sensitized to or resistant to diabetes.
- Published
- 2014
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29. NAD as a Genotype-Specific Drug Target.
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Mei, Szu-Chieh and Brenner, Charles
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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
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30. Discovery of two eukaryotic nicotinamide riboside salvage pathways: New nutritional approaches to promote Sir2 function.
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Brenner, Charles
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NICOTINAMIDE , *YEAST , *CELLS , *NAD (Coenzyme) , *ENZYMES , *GENE silencing - Abstract
We recently discovered that nicotinamide riboside, previously thought to be a bacterial NAD precursor, is a vitamin precursor of NAD in yeast and humans, which is converted to NAD in a pathway initiated by specific nicotinamide riboside kinases. Nicotinamide riboside has been shown to allow dorsal ganglion root neurons to resist axonopathy and the nicotinamide riboside kinase 2 gene has been shown to be induced by damage. In this study, we describe a second biosynthetic pathway for nicotinamide riboside salvage in yeast and human cells. We establish the conditions in which yeast cells take up the compound and convert it to NAD and we show that both of the newly identified nicotinamide riboside salvage pathways increase Sir2 activity in gene silencing and promote yeast cell longevity in the absence of calorie restriction. [ABSTRACT FROM AUTHOR]
- Published
- 2007
31. Finding Criminals Through DNA of Their Relatives.
- Author
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Bieber, Frederick R., Brenner, Charles H., and Lazer, David
- Subjects
- *
FORENSIC sciences , *DNA fingerprinting , *DATABASES , *CRIMINALS , *FORENSIC genetics techniques , *CRIMINAL investigation , *IDENTIFICATION , *GOVERNMENT policy , *STATUTES - Abstract
The article discusses various issues related to the use of DNA methods for forensic purposes. Every U.S. states and nearly every industrialized country maintains DNA databases of convicted offenders. These databases allow comparison of crime scene DNA profiles to one another and to known offenders. The policy of government of Great Britain stipulates that almost any violation of law enforcement results in the collection of DNA of the violator. The U.S. government has more that 3 million samples of offender/arrestee in their state and federal DNA databases. Different states of the U.S. have different statutes governing the use of these samples and protection against misuse. Direct comparisons of DNA profiles of known individuals and unknown biological evidence commonly used to identify individuals. Indirect genetic kinship analyses, using the DNA of biological relatives are often necessary for humanitarian mass disaster and missing person identifications.
- Published
- 2006
- Full Text
- View/download PDF
32. Evolution of NAD Biosynthetic Enzymes
- Author
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Brenner, Charles
- Subjects
- *
NIACIN , *CARBOXYLIC acids , *BIOCHEMICAL engineering , *BIOCHEMISTRY - 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 (). [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
33. Jacob A. Arlow (1912-2004).
- Author
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Brenner C and Brenner, Charles
- Published
- 2006
- Full Text
- View/download PDF
34. Jacob A. Arlow (1912-2004).
- Author
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Brenner, Charles
- Subjects
- ARLOW, Jacob A.
- Abstract
The article presents an obituary for psychiatrist Jacob A. Arlow.
- Published
- 2006
- Full Text
- View/download PDF
35. Condensing the RNA world.
- Author
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Brenner, Charles
- Subjects
- *
RNA , *MACROMOLECULES , *RIBOSOMES - Abstract
Discusses studies on the structure of ribosomal RNA. Information on 23S RNA macromolecule; Factor that underscores the impression of the large-subunit structure that polypeptides stabilize 23S RNA; Implication of the crystal structures of substrate analogs for peptide transfer bound by RNA.
- Published
- 2000
- Full Text
- View/download PDF
36. Revolution in Mind: The Creation of Psychoanalysis.
- Author
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Brenner, Charles
- Subjects
- *
PSYCHOANALYSIS , *NONFICTION - Abstract
The article reviews the book "Revolution in Mind: The Creation of Psychoanalysis," by George Makari.
- Published
- 2008
- Full Text
- View/download PDF
37. Metabolic rescue ameliorates mitochondrial encephalo‐cardiomyopathy in murine and human iPSC models of Leigh syndrome.
- Author
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Yoon, Jin‐Young, Daneshgar, Nastaran, Chu, Yi, Chen, Biyi, Hefti, Marco, Vikram, Ajit, Irani, Kaikobad, Song, Long‐Sheng, Brenner, Charles, Abel, E. Dale, London, Barry, and Dai, Dao‐Fu
- Subjects
- *
PLURIPOTENT stem cells , *INDUCED pluripotent stem cells , *HEART , *KREBS cycle , *MITOCHONDRIA , *SODIUM channels - Abstract
Background: Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio‐encephalomyopathy in LS remains incompletely understood. Methods: We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells‐derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency. Results: LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human‐induced pluripotent stem cell‐derived cardiomyocytes (iPS‐CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD+/NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+‐dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+‐dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV1.5 current and SERCA2a function measured by Ca2+‐transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS‐derived neurons with Ndufs4 deletion. Conclusions: Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
38. Extensive evaluation of DNA polymerase performance for highly degraded human DNA samples.
- Author
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Kijeong Kim, Bazarragchaa, Munkhtsetseg, Brenner, Charles H., Byung-Sun Choi, and Kyung-Yong Kim
- Subjects
- *
DNA polymerases , *FORENSIC sciences , *POLYMERASE chain reaction , *GEL electrophoresis , *AGAROSE - Abstract
Highly degraded human DNA is commonly encountered in the forensic studies. Despite many efforts, the poor quality and quantity of the DNA often result in unsuccessful DNA analysis. There has been no extensive evaluation of DNA polymerase performance for the successful PCR of highly degraded DNA samples. We evaluated the most efficient DNA polymerases, based on real-time PCR and agarose gel electrophoresis analyses for a single copy gene amplification, with 200 ancient DNA (aDNA) samples of various origins. Nine commercially available DNA polymerases were tested, which included enzymes that are reportedly effective for PCR-inhibitory samples. The first screening test for the polymerases with 20 aDNA samples showed that Pico Maxx HF, FastStart Taq, and Ex Taq HS DNA polymerases were the most effective. Further tests with 180 aDNA samples showed that AmpliTaq Gold (control) amplified PCR products from 52 aDNA samples, PicoMaxx HF from 62, FastStart Taq from 64, and Ex Taq HS from 65. The use of two or more of Ex Taq HS, FastStart Taq, and PicoMaxx HF resulted in a significantly higher success rate than that of AmpliTaq Gold alone. With 37 positive samples tested in duplicate, Ex Taq HS showed the highest reproducibility (13 samples) and AmpliTaq Gold, the lowest (four samples); this difference was significant. The data also showed preferential amplification by the enzymes; Ex Taq HS exclusively produced amplification from two samples, FastStart Taq from one, and PicoMaxx HF from one. We suggest that the initial use of these three DNA polymerases will increase the probability of successfully amplifying DNA from highly degraded human DNA samples. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
39. RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation.
- Author
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Wu, Bo-Kuan, Mei, Szu-Chieh, and Brenner, Charles
- Published
- 2014
- Full Text
- View/download PDF
40. Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.
- Author
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Jing Wu, Singh, Komudi, Lin, Amy, Meadows, Allison M., Kaiyuan Wu, Shing, Vivian, Bley, Maximilian, Hassanzadeh, Shahin, Huffstutler, Rebecca D., Schmidt, Mark S., Blanco, Luz P., Rong Tian, Brenner, Charles, Pirooznia, Mehdi, Kaplan, Mariana J., Sack, Michael N., Wu, Jing, Wu, Kaiyuan, and Tian, Rong
- Subjects
- *
SYSTEMIC lupus erythematosus , *MONOCYTES , *AUTOPHAGY , *MYELOID cells , *CD14 antigen , *CYTOLOGY , *LIPOPOLYSACCHARIDES , *NUCLEOSIDES , *GLYCOSIDES , *CELL receptors , *COENZYMES , *VITAMIN B complex , *INTERFERONS , *RESEARCH funding - Abstract
BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-β production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-β release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-β release.CONCLUSIONWe conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
41. Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: Chemical and metabolic logic of acetyl-lysine modifications.
- Author
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Ghanta, Sirisha, Grossmann, Ruth E., and Brenner, Charles
- Subjects
- *
MITOCHONDRIAL proteins , *ACETYLATION , *ACETYL compounds , *LYSINE , *HORMONES , *LOW-calorie diet , *LIPID synthesis , *BIOLOGICAL evolution - Abstract
Hormone systems evolved over 500 million years of animal natural history to motivate feeding behavior and convert excess calories to fat. These systems produced vertebrates, including humans, who are famine-resistant but sensitive to obesity in environments of persistent overnutrition. We looked for cell-intrinsic metabolic features, which might have been subject to an evolutionary drive favoring lipogenesis. Mitochondrial protein acetylation appears to be such a system. Because mitochondrial acetyl-coA is the central mediator of fuel oxidation and is saturable, this metabolite is postulated to be the fundamental indicator of energy excess, which imprints a memory of nutritional imbalances by covalent modification. Fungal and invertebrate mitochondria have highly acetylated mitochondrial proteomes without an apparent mitochondrially targeted protein lysine acetyltransferase. Thus, mitochondrial acetylation is hypothesized to have evolved as a nonenzymatic phenomenon. Because the p Ka of a nonperturbed Lys is 10.4 and linkage of a carbonyl carbon to an ℇ amino group cannot be formed with a protonated Lys, we hypothesize that acetylation occurs on residues with depressed p Ka values, accounting for the propensity of acetylation to hit active sites and suggesting that regulatory Lys residues may have been under selective pressure to avoid or attract acetylation throughout animal evolution. In addition, a shortage of mitochondrial oxaloacetate under ketotic conditions can explain why macronutrient insufficiency also produces mitochondrial hyperacetylation. Reduced mitochondrial activity during times of overnutrition and undernutrition would improve fitness by virtue of resource conservation. Micronutrient insufficiency is predicted to exacerbate mitochondrial hyperacetylation. Nicotinamide riboside and Sirt3 activity are predicted to relieve mitochondrial inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
42. Evaluating Mixture Solution™— rapid and non-MCMC probabilistic mixture analysis.
- Author
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Lucassen, Anton, Ehlers, Karen, Grobler, Paul J., and Brenner, Charles H.
- Subjects
- *
POLICE services , *DNA data banks , *SEX crimes , *SEXUAL assault , *DNA analysis , *MIXTURES - Abstract
We compare DNA mixture analysis via DNAˑVIEW® Mixture Solution™ and the current combined probability of inclusion (CPI) method of the South African Police Service (SAPS). South Africa has a high incidence of property-related crimes and sexual offences and consequently a great deal of low-template (LT-DNA) forensic DNA mixture casework and a perpetual backlog. A range of casework and laboratory-prepared sexual assault mixtures with initial male DNA amounts varying from about 2 to 200 cells were analysed to evaluate the benefits of a continuous model program. Unfortunately CPI methods are nearly useless for LT-DNA cases because of dropout—common from a mixture contribution of fewer than 20 or 30 cells. We further argue that proposed CPI elaborations to circumvent dropout lack supporting research or even explanation. Mixture Solution models mixture data as continuous rather than binary, with a mathematically coherent ("probabilistic") model which incorporates dropout and other phenomena realistically. Much more information is thereby utilised resulting in applicability to more cases (7 or fewer contributor cells suffice), stronger evidence against a suspect who is a mixture contributor and stronger evidence to absolve a non-contributor. Mixture Solution incidentally provides information which, along with rfu data, allows estimating contributions in terms of number of cells, which is a useful perspective. The method of calculation is explained. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
43. Saccharomyces cerevisiae YOR071C Encodes the High Affinity Nicotinamide Riboside Transporter Nrt1.
- Author
-
Belenky, Peter A., Moga, Tiberiu G., and Brenner, Charles
- Subjects
- *
SACCHAROMYCES , *ENZYMES , *NICOTINAMIDE , *NIACIN , *YEAST , *POLYPEPTIDES - Abstract
NAD+ is an essential coenzyme for hydride transfer enzymes and a substrate of sirtuins and other NAD+-consuming enzymes. Nicotinamide riboside is a recently discovered eukaryotic NAD+ precursor converted to NAD+ via the nicotinamide riboside kinase pathway and by nucleosidase activity and nicotinamide salvage. Nicotinamide riboside supplementation of yeast extends replicative life span on high glucose medium. The molecular basis for nicotinamide riboside uptake was unknown in any eukaryote. Here, we show that deletion of a single gene, YOR071C, abrogates nicotinamide riboside uptake without altering nicotinic acid or nicotinamide import. The gene, which is negatively regulated by Sum!, Hst1, and Rfm1, fully restores nicotinamide riboside import and utilization when resupplied to mutant yeast cells. The encoded polypeptide, Nrt1, is a predicted deca-spanning membrane protein related to the thiamine transporter, which functions as a pH-dependent facilitator with a Km for nicotinamide riboside of 22 µM. Nrt1-related molecules are conserved in particular fungi, suggesting a similar basis for nicotinamide riboside uptake. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
44. NAD+ metabolism in health and disease
- Author
-
Belenky, Peter, Bogan, Katrina L., and Brenner, Charles
- Subjects
- *
COENZYMES , *ENZYMES , *ADENOSINE diphosphate , *RIBOSE , *CANDIDA - Abstract
Nicotinamide adenine dinucleotide (NAD+) is both a coenzyme for hydride-transfer enzymes and a substrate for NAD+-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for NAD+ that might be applicable therapeutically to prevent neurodegenerative conditions and to fight Candida glabrata infection. In addition, the contribution that NAD+ metabolism makes to lifespan extension in model systems indicates that therapies to boost NAD+ might promote some of the beneficial effects of calorie restriction. Nicotinamide riboside, the recently discovered nucleoside precursor of NAD+ in eukaryotic systems, might have advantages as a therapy to elevate NAD+ without inhibiting sirtuins, which is associated with high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
45. Disease-associated Mutations Inactivate AMP-Lysine Hydrolase Activity of Aprataxin.
- Author
-
Seidle, Heather F., Bieganowski, Pawel, and Brenner, Charles
- Subjects
- *
LYSINE , *PROTEIN-protein interactions , *HYDROLASES , *ENZYMES , *GENETIC mutation , *DNA damage , *ATAXIA , *PSYCHOMOTOR disorders , *DNA - Abstract
Ataxia-oculomotor apraxia syndrome 1 is an early onset cerebellar ataxia that results from loss of function mutations in the APTX gene, encoding Aprataxin, which contains three conserved domains. The forkhead-associated domain of Aprataxin mediates protein-protein interactions with molecules that respond to DNA damage, but the cellular phenotype of the disease does not appear to be consistent with a major loss in DNA damage responses. Disease-associated mutations in Aprataxin target a histidine triad domain that is similar to Hint, a universally conserved AMP-lysine hydrolase, or truncate the protein NH2-terminal to a zinc finger. With novel fluorigenic substrates, we demonstrate that Aprataxin possesses an active-site-dependent AMP-lysine and GMP-lysine hydrolase activity that depends additionally on the zinc finger for protein stability and on the forkhead associated domain for enzymatic activity. Alleles carrying any of eight recessive mutations associated with ataxia and oculomotor apraxia encode proteins with huge losses in protein stability and enzymatic activity, consistent with a null phenotype. The mild presentation allele, APTX-K197Q, associated with ataxia but not oculomotor apraxia, encodes a protein with a mild defect in stability and activity, while enzyme encoded by the atypical presentation allele, APTXR199H, retained substantial function, consistent with altered and not loss of activity. The data suggest that the essential function of Aprataxin is reversal of nucleotidylylated protein modifications, that all three domains contribute to formation of a stable enzyme, and that the in vitro behavior of cloned APTX alleles can score disease-associated mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
46. Eukaryotic NAD[sup +] Synthetase Qns1 Contans an Essential, Obligate Intramolecular Thiol Glutamine Amidotransferase Domain Related to Nitrilase.
- Author
-
Bieganowski, Pawel, Pace, Helen C., and Brenner, Charles
- Subjects
- *
NAD (Coenzyme) , *LIGASES , *EUKARYOTIC cells , *GLUTAMINE , *GLUTAMINE amidotransferase - Abstract
NAD[sup +] is an essential co-enzyme for redox reactions and is consumed in lysine deacetylation and poly(ADPribosyl)ation. NAD[sup +] synthetase catalyzes the final step in NAD[sup +] synthesis in the well characterized de novo, salvage, and import pathways. It has been long known that eukaryotic NAD[sup +] synthetases use glutamine to amidate nicotinic acid adenine dinucleotide while many purified prokaryotic NAD[sup +] synthetases are ammonia-dependent. Earlier, we discovered that glutamine-dependent NAD[sup +] synthetases contain N-terminal domains that are members of the nitrilase superfamily and hypothesized that these domains function as glutamine amidotransferases for the associated synthetases. Here we show yeast glutamine-dependent NAD[sup +] synthetase Qns1 requires both the nitrilase-related active-site residues and the NAD[sup +] synthetase active-site residues for function in vivo. Despite failure to complement the lethal phenotype of qns1 disruption, the former mutants retain ammonia-dependent NAD[sup +] synthetase activity in vitro, whereas the latter mutants retain basal glutaminase activity. Moreover, the two classes of mutants fail to trans-complement despite forming a stable heteromultimer in vivo. These data indicate that the nitrilase-related domain in Qns1 is the fourth independently evolved glutamine amidotransferase domain to have been identified in nature and that glutamine-dependence is an obligate phenomenon involving intramolecular transfer of ammonia over a predicted distance of 46 Å from one active site to another within Qns1 monomers. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
47. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD+.
- Author
-
Jureepon Roboon, Tsuyoshi Hattori, Hiroshi Ishii, Mika Takarada-Iemata, Dinh Thi Nguyen, Heer, Collin D., O'Meally, Denis, Brenner, Charles, Yasuhiko Yamamoto, Hiroshi Okamoto, Haruhiro Higashida, and Hori, Osamu
- Subjects
- *
NAD (Coenzyme) , *NEUROINFLAMMATION , *MICROGLIA , *NICOTINAMIDE , *CALCIUM metabolism , *ALZHEIMER'S disease , *INFLAMMATION - Abstract
Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone-induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)-induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
48. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide‐induced microglial and astrocytic neuroinflammation by increasing NAD+.
- Author
-
Roboon, Jureepon, Hattori, Tsuyoshi, Ishii, Hiroshi, Takarada‐Iemata, Mika, Nguyen, Dinh Thi, Heer, Collin D., O'Meally, Denis, Brenner, Charles, Yamamoto, Yasuhiko, Okamoto, Hiroshi, Higashida, Haruhiro, and Hori, Osamu
- Subjects
- *
NAD (Coenzyme) , *NEUROINFLAMMATION , *MICROGLIA , *NICOTINAMIDE , *CALCIUM metabolism , *ALZHEIMER'S disease , *INFLAMMATION - Abstract
Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone‐induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)‐induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS‐induced inflammatory responses and glial activation. Pre‐administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS‐induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF‐κB signaling pathway in microglia. These results suggest that CD38‐mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
49. Mechanisms to reduce the cytotoxicity of pharmacological nicotinamide concentrations in the pathogenic fungus Candida albicans.
- Author
-
Ghugari, Rahul, Tsao, Sarah, Schmidt, Mark, Bonneil, Éric, Brenner, Charles, and Verreault, Alain
- Subjects
- *
PATHOGENIC fungi , *NAD (Coenzyme) , *CANDIDA albicans , *NICOTINAMIDE , *NIACIN , *SIRTUINS , *EXCHANGE reactions , *RADIOLABELING - Abstract
Candida albicans is a pathogenic fungus that causes systemic infections and mortality in immunosuppressed individuals. We previously showed that deacetylation of histone H3 lysine 56 by Hst3 is essential for C. albicans viability. Hst3 is a fungal‐specific NAD+‐dependent protein deacetylase of the sirtuin family. In vivo, supraphysiological concentrations of nicotinamide (NAM) are required for Hst3 inhibition and cytotoxicity. This underscores the importance of identifying mechanisms by which C. albicans can modulate intracellular NAM concentrations. For the first time in a pathogenic fungus, we combine genetics, heavy isotope labeling, and targeted quantitative metabolomics to identify genes, pathways, and mechanisms by which C. albicans can reduce the cytotoxicity of high NAM concentrations. We discovered three distinct fates for supraphysiological NAM concentrations. First, upon transient exposure to NAM, high intracellular NAM concentrations rapidly return near the physiological levels observed in cells that are not exposed to NAM. Second, during the first step of a fungal‐specific NAM salvage pathway, NAM is converted into nicotinic acid, a metabolite that cannot inhibit the sirtuin Hst3. Third, we provide evidence that NAM enters the NAD+ metabolome through a NAM exchange reaction that contributes to NAM‐mediated inhibition of sirtuins. However, in contrast to the other fates of NAM, the NAM exchange reaction cannot cause a net decrease in the intracellular concentration of NAM. Therefore, this reaction cannot enhance resistance to NAM. In summary, we demonstrate that C. albicans possesses at least two mechanisms to attenuate the cytotoxicity of pharmacological NAM concentrations. It seems likely that those two mechanisms of resistance to cytotoxic NAM concentrations are conserved in many other pathogenic fungi. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
50. Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity.
- Author
-
Heer, Collin D., Sanderson, Daniel J., Voth, Lynden S., Alhammad, Yousef M. O., Schmidt, Mark S., Trammell, Samuel A. J., Perlman, Stanley, Cohen, Michael S., Fehr, Anthony R., and Brenner, Charles
- Subjects
- *
CORONAVIRUS diseases , *COVID-19 , *POLY(ADP-ribose) polymerase , *NATURAL immunity , *NICOTINAMIDE , *VIRAL hepatitis , *NAD (Coenzyme) - Abstract
Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD1 and NADP1. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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